1 4348 156 MIR-146A DYSREGULATES ENERGY METABOLISM DURING NEUROINFLAMMATION. ALZHEIMER'S DISEASE (AD) AND OTHER NEURODEGENERATIVE DISEASES ARE CHARACTERIZED BY CHRONIC NEUROINFLAMMATION AND A REDUCTION IN BRAIN ENERGY METABOLISM. AN IMPORTANT ROLE HAS EMERGED FOR SMALL, NON-CODING RNA MOLECULES KNOWN AS MICRORNAS (MIRNAS) IN THE PATHOPHYSIOLOGY OF MANY NEURODEGENERATIVE DISORDERS. AS EPIGENETIC REGULATORS, MIRNAS POSSESS THE CAPACITY TO REGULATE AND FINE TUNE PROTEIN PRODUCTION BY INHIBITING TRANSLATION. SEVERAL MIRNAS, WHICH INCLUDE MIR-146A, ARE ELEVATED IN THE BRAIN, CSF, AND PLASMA OF AD PATIENTS. MIR-146A PARTICIPATES IN PATHWAYS THAT REGULATE IMMUNE ACTIVATION AND HAS SEVERAL MRNA TARGETS WHICH ENCODE FOR PROTEINS INVOLVED IN CELLULAR ENERGY METABOLISM. AN ADDITIONAL ROLE FOR EXTRACELLULAR VESICLES (EVS) HAS ALSO EMERGED IN THE PROGRESSION AD, AS EVS CAN TRANSFER FUNCTIONALLY ACTIVE PROTEINS AND RNAS FROM DISEASED TO HEALTHY CELLS. IN THE CURRENT STUDY, WE EXPOSED VARIOUS CELL TYPES PRESENT WITHIN THE CNS TO IMMUNOMODULATORY MOLECULES AND OBSERVED SIGNIFICANT UPREGULATION OF MIR-146A EXPRESSION, BOTH WITHIN CELLS AND WITHIN THEIR SECRETED EVS. FURTHER, WE ASSESSED THE EFFECTS OF MIR-146A OVEREXPRESSION ON BIOENERGETIC FUNCTION IN PRIMARY RAT GLIAL CELLS AND FOUND SIGNIFICANT REDUCTIONS IN OXIDATIVE PHOSPHORYLATION AND GLYCOLYSIS. LASTLY, WE CORRELATED MIR-146A EXPRESSION LEVELS WITHIN VARIOUS REGIONS OF THE AD BRAIN TO DISEASE STAGING AND FOUND SIGNIFICANT, POSITIVE CORRELATIONS. THESE NOVEL RESULTS DEMONSTRATE THAT THE MODULATION OF MIR-146A IN RESPONSE TO NEUROINFLAMMATORY STIMULI MAY MEDIATE THE LOSS OF MITOCHONDRIAL INTEGRITY AND FUNCTION IN CELLS, THEREBY CONTRIBUTING TO THE PROGRESSION OF BETA-AMYLOID AND TAU PATHOLOGY IN THE AD BRAIN. MULTIPLE INFLAMMATORY STIMULI CAN UPREGULATE MIRNA-146A EXPRESSION WITHIN NEURONS, MIXED GLIAL CELLS, AND BRAIN ENDOTHELIAL CELLS, WHICH IS EITHER RETAINED WITHIN THESE CELLS OR RELEASED FROM THEM AS EXTRACELLULAR VESICLE CARGO. THE UPREGULATION OF MIR-146A DISRUPTS CELLULAR BIOENERGETICS IN MIXED GLIAL CELLS. THIS MECHANISM MAY PLAY A CRITICAL ROLE IN THE NEUROINFLAMMATORY RESPONSE OBSERVED DURING ALZHEIMER'S DISEASE. 2022 2 4333 59 MICRORNAS: KEY PLAYERS IN MICROGLIA AND ASTROCYTE MEDIATED INFLAMMATION IN CNS PATHOLOGIES. THE SIGNIFICANCE OF MICROGLIA AND ASTROCYTES IN NEURAL DEVELOPMENT, IN MAINTAINING SYNAPTIC CONNECTIONS AND HOMEOSTASIS IN THE HEALTHY BRAIN IS WELL ESTABLISHED. MICROGLIA ARE DYNAMIC IMMUNE CELLS OF THE BRAIN THAT ELICIT AN IMMUNE RESPONSE DURING BRAIN DAMAGE AND ALSO PARTICIPATE IN TISSUE REPAIR AND REGENERATION, WHILE ASTROCYTES CONTRIBUTE TO THE LOCAL INFLAMMATORY RESPONSE BY PRODUCING PROINFLAMMATORY CYTOKINES AND RESOLVING NEURONAL DAMAGE THROUGH PRODUCTION OF ANTI-INFLAMMATORY CYTOKINES AND NEUROTROPHIC FACTORS. RECENT EFFORTS HAVE FOCUSED ON ELUCIDATING THE EPIGENETIC MECHANISMS WHICH REGULATE GLIAL CELL BEHAVIOR IN NORMAL AND PATHOLOGIC STATES. AN IMPORTANT CLASS OF EPIGENETIC REGULATORS IS MICRORNAS (MIRNAS) WHICH ARE SMALL NON-CODING RNA MOLECULES THAT REGULATE GENE EXPRESSION POSTTRANSCRIPTIONALLY. CERTAIN DYSREGULATED MIRNAS CONTRIBUTE TO CHRONIC MICROGLIAL INFLAMMATION IN THE BRAIN, THEREBY LEADING TO PROGRESSION OF NEUROLOGICAL DISEASES LIKE ALZHEIMER'S DISEASE, TRAUMATIC INJURY, AMYOTROPHIC LATERAL SCLEROSIS AND STROKE. FURTHER, SEVERAL MIRNAS ARE DIFFERENTIALLY EXPRESSED IN ASTROCYTES AFTER ISCHEMIA AND SPINAL CORD INJURY. DESPITE KNOWLEDGE ABOUT MIRNAS IN NEUROINFLAMMATION, LITTLE IS KNOWN ABOUT EFFECTIVE DELIVERY ROUTES AND PHARMACOKINETIC DATA FOR MIRNA BASED THERAPEUTICS. THIS REVIEW SUMMARIZES THE CURRENT RESEARCH ON THE ROLE OF MIRNAS IN PROMOTING AND INHIBITING INFLAMMATORY RESPONSE OF MICROGLIA AND ASTROCYTES IN A DISEASE-SPECIFIC MANNER. IN ADDITION, MIRNA DELIVERY AS A THERAPEUTIC STRATEGY TO TREAT NEUROINFLAMMATION IS DISCUSSED. 2016 3 4372 50 MIRNAS, OXIDATIVE STRESS, AND CANCER: A COMPREHENSIVE AND UPDATED REVIEW. OXIDATIVE STRESS REFERS TO ELEVATED LEVELS OF INTRACELLULAR REACTIVE OXYGEN SPECIES (ROS). ROS HOMEOSTASIS FUNCTIONS AS A SIGNALING PATHWAY FOR NORMAL CELL SURVIVAL AND APPROPRIATE CELL SIGNALING. CHRONIC INFLAMMATION INDUCED BY IMBALANCED LEVELS OF ROS CONTRIBUTES TO MANY DISEASES AND DIFFERENT TYPES OF CANCER. ROS CAN ALTER THE EXPRESSION OF ONCOGENES AND TUMOR SUPPRESSOR GENES THROUGH EPIGENETIC MODIFICATIONS, TRANSCRIPTION FACTORS, AND NON-CODING RNAS. MICRORNAS (MIRNAS) ARE SMALL NON-CODING RNAS THAT PLAY A KEY ROLE IN MOST BIOLOGICAL PATHWAYS. EACH MIRNA REGULATES HUNDREDS OF TARGET GENES BY INHIBITING PROTEIN TRANSLATION AND/OR PROMOTING MESSENGER RNA DEGRADATION. IN NORMAL CONDITIONS, MIRNAS PLAY A PHYSIOLOGICAL ROLE IN CELL PROLIFERATION, DIFFERENTIATION, AND APOPTOSIS. HOWEVER, DIFFERENT FACTORS THAT CAN DYSREGULATE CELL SIGNALING AND CELLULAR HOMEOSTASIS CAN ALSO AFFECT MIRNA EXPRESSION. THE ALTERATION OF MIRNA EXPRESSION CAN WORK AGAINST DISTURBING FACTORS OR MEDIATE THEIR EFFECTS. OXIDATIVE STRESS IS ONE OF THESE FACTORS. CONSIDERING THE COMPLEX INTERPLAY BETWEEN ROS LEVEL AND MIRNA REGULATION AND BOTH OF THESE WITH CANCER DEVELOPMENT, WE REVIEW THE ROLE OF MIRNAS IN CANCER, FOCUSING ON THEIR FUNCTION IN OXIDATIVE STRESS. 2020 4 4278 41 MICROGLIAL INNATE MEMORY AND EPIGENETIC REPROGRAMMING IN NEUROLOGICAL DISORDERS. MICROGLIA ARE MYELOID-DERIVED CELLS RECOGNIZED AS BRAIN-RESIDENT MACROPHAGES. THEY ACT AS THE FIRST AND MAIN LINE OF IMMUNE DEFENSE IN THE CENTRAL NERVOUS SYSTEM (CNS). MICROGLIA HAVE HIGH PHENOTYPIC PLASTICITY AND ARE ESSENTIAL FOR REGULATING HEALTHY BRAIN HOMEOSTASIS, AND THEIR DYSREGULATION UNDERLIES THE ONSET AND PROGRESSION OF SEVERAL CNS PATHOLOGIES THROUGH IMPAIRED INFLAMMATORY RESPONSES. ABERRANT MICROGLIAL ACTIVATION, FOLLOWING AN INFLAMMATORY INSULT, IS ASSOCIATED WITH EPIGENETIC DYSREGULATION IN VARIOUS CNS PATHOLOGIES. EMERGING DATA SUGGEST THAT CERTAIN STIMULI TO MYELOID CELLS DETERMINE ENHANCED OR ATTENUATED RESPONSES TO SUBSEQUENT STIMULI. THESE PHENOMENA, GENERALLY TERMED INNATE IMMUNE MEMORY (IIM), ARE HIGHLY DEPENDENT ON EPIGENETIC REPROGRAMMING. MICROGLIAL PRIMING HAS BEEN REPORTED IN SEVERAL NEUROLOGICAL DISEASES AND CORRESPONDS TO A STATE OF INCREASED PERMISSIVENESS OR EXACERBATED RESPONSE, PROMOTED BY CONTINUOUS EXPOSURE TO A CHRONIC PRO-INFLAMMATORY ENVIRONMENT. IN THIS ARTICLE, WE PROVIDE EXTENSIVE EVIDENCE OF THESE EPIGENETIC-MEDIATED PHENOMENA UNDER NEUROLOGICAL CONDITIONS AND DISCUSS THEIR CONTRIBUTION TO PATHOGENESIS AND THEIR CLINICAL IMPLICATIONS, INCLUDING THOSE CONCERNING POTENTIAL NOVEL THERAPEUTIC APPROACHES. 2021 5 6701 44 VASCULAR FACTORS AND EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS A DEBILITATING ILLNESS WITH NO KNOWN CURE. NOWADAYS ACCUMULATING EVIDENCE SUGGESTED THAT THE VASCULAR ENDOTHELIUM AND CHRONIC HYPOPERFUSION MAY PLAY IMPORTANT ROLE IN PATHOBIOLOGY OF AD. THE VASCULAR ENDOTHELIUM WHICH REGULATES THE PASSAGE OF MACROMOLECULES AND CIRCULATING CELLS FROM BLOOD TO TISSUE, IS A MAJOR TARGET OF OXIDATIVE STRESS, PLAYING A CRITICAL ROLE IN THE PATHOPHYSIOLOGY OF VASCULAR DISEASES. SINCE THE VASCULAR ENDOTHELIUM, NEURONS AND GLIA ARE ALL ABLE TO SYNTHESIZE, STORE AND RELEASE REACTIVE OXYGEN SPECIES (ROS) AND VASCULAR ACTIVE SUBSTANCES IN RESPONSE TO CERTAIN STIMULI, THEIR CONTRIBUTION TO THE PATHOPHYSIOLOGY OF AD CAN BE VERY IMPORTANT. NEW EVIDENCE INDICATES THAT CONTINUOUS FORMATION OF FREE ROS INDUCES CELLULAR DAMAGE AND DECREASES ANTIOXIDANT DEFENSES. SPECIFICALLY, OXIDATIVE STRESS INCREASES VASCULAR ENDOTHELIAL PERMEABILITY AND PROMOTES LEUKOCYTE ADHESION. WE SUMMARIZE THE REPORTS THAT SPORADIC, LATE-ONSET OF AD RESULTS FROM VASCULAR ETIOLOGY. RECENTLY AN INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE ETIOLOGY OF AD IS ALSO INTENSIVELY INVESTIGATED. GAINING A MORE COMPLETE UNDERSTANDING OF THE ESSENTIAL COMPONENTS AND UNDERLYING MECHANISMS INVOLVED IN EPIGENETIC REGULATION COULD LEAD TO NOVEL TREATMENTS FOR A NUMBER OF NEUROLOGICAL AND PSYCHIATRIC CONDITIONS. 2012 6 6533 36 TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES ASSOCIATED WITH SEVERE ASTHMA. THE 10% OF PATIENTS WITH THE MOST SEVERE ASTHMA ARE RESPONSIBLE FOR A LARGE PART OF HEALTHCARE EXPENDITURE AND MORBIDITY. UNDERSTANDING THE PROCESSES INVOLVED IS KEY IF NEW THERAPEUTIC APPROACHES ARE TO BE DEVELOPED. EVIDENCE IS ACCUMULATING THAT CHRONIC DISEASES SUCH AS ASTHMA ARE ASSOCIATED WITH TEMPORAL AND SPATIAL ALTERATIONS IN THE PATTERN OF INFLAMMATORY GENE EXPRESSION WITHIN THE AIRWAYS. EXPRESSION OF THESE GENES CAN BE REGULATED BY TRANSCRIPTIONAL, POSTTRANSCRIPTIONAL, TRANSLATIONAL AND EPIGENETIC MECHANISMS. IT IS WELL ESTABLISHED THAT BINDING OF ACTIVATED TRANSCRIPTION FACTORS TO SPECIFIC INDUCIBLE GENE PROMOTER SITES IS TIGHTLY CONTROLLED BY CHROMATIN STATE AS A RESULT OF HISTONE MODIFICATIONS, PARTICULARLY THE BALANCE BETWEEN HISTONE ACETYLATION AND DEACETYLATION [1]. THE INTERACTION BETWEEN TRANSCRIPTION FACTORS AND THE PROMOTER IS KEY TO THE DIVERSIFICATION OF GENE EXPRESSION IN A TIME DEPENDENT MANNER LEADING TO ALTERED GENE EXPRESSION PROFILES. ALTERATIONS OF THE ACCESSIBILITY OF TRANSCRIPTION FACTORS TO THE DNA CAN HAVE RESIDING EFFECTS UPON GENE TRANSCRIPTION. THIS REVIEW WILL FOCUS ON THE REGULATION OF SEVERAL GROUPS OF KEY GENES WHICH ARE INVOLVED IN CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA DRAWING MAINLY FROM OUR EXPERIENCE OF STUDYING THESE PROCESSES IN AIRWAY SMOOTH MUSCLE CELLS. AN OVERVIEW IS SHOWN IN FIGURE 1. 2011 7 6527 44 TRANSCRIPTIONAL CONTROL OF MALADAPTIVE AND PROTECTIVE RESPONSES IN ALCOHOLICS: A ROLE OF THE NF-KAPPAB SYSTEM. ALCOHOL DEPENDENCE AND ASSOCIATED COGNITIVE IMPAIRMENT APPEAR TO RESULT FROM MALADAPTIVE NEUROPLASTICITY IN RESPONSE TO CHRONIC ALCOHOL CONSUMPTION, NEUROINFLAMMATION AND NEURODEGENERATION. THE INHERENT STABILITY OF BEHAVIORAL ALTERATIONS ASSOCIATED WITH THE ADDICTED STATE SUGGESTS THAT TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS ARE OPERATIVE. NF-KAPPAB TRANSCRIPTION FACTORS ARE REGULATORS OF SYNAPTIC PLASTICITY AND INFLAMMATION, AND RESPONSIVE TO A VARIETY OF STIMULI INCLUDING ALCOHOL. THESE FACTORS ARE ABUNDANT IN THE BRAIN WHERE THEY HAVE DIVERSE FUNCTIONS THAT DEPEND ON THE COMPOSITION OF THE NF-KAPPAB COMPLEX AND CELLULAR CONTEXT. IN NEURON CELL BODIES, NF-KAPPAB IS CONSTITUTIVELY ACTIVE, AND INVOLVED IN NEURONAL INJURY AND NEUROPROTECTION. HOWEVER, AT THE SYNAPSE, NF-KAPPAB IS PRESENT IN A LATENT FORM AND UPON ACTIVATION IS TRANSPORTED TO THE CELL NUCLEUS. IN GLIA, NF-KAPPAB IS INDUCIBLE AND REGULATES INFLAMMATORY PROCESSES THAT EXACERBATE ALCOHOL-INDUCED NEURODEGENERATION. ANIMAL STUDIES DEMONSTRATE THAT ACUTE ALCOHOL EXPOSURE TRANSIENTLY ACTIVATES NF-KAPPAB, WHICH INDUCES NEUROINFLAMMATORY RESPONSES AND NEURODEGENERATION. POSTMORTEM STUDIES OF BRAINS OF HUMAN ALCOHOLICS SUGGEST THAT REPEATED CYCLES OF ALCOHOL CONSUMPTION AND WITHDRAWAL CAUSE ADAPTIVE CHANGES IN THE NF-KAPPAB SYSTEM THAT MAY PERMIT THE SYSTEM TO BETTER TOLERATE EXCESSIVE STIMULATION. THIS TYPE OF TOLERANCE, ENSURING A LOW DEGREE OF RESPONSIVENESS TO APPLIED STIMULI, APPARENTLY DIFFERS FROM THAT IN THE IMMUNE SYSTEM, AND MAY REPRESENT A COMPENSATORY RESPONSE THAT PROTECTS BRAIN CELLS AGAINST ALCOHOL NEUROTOXICITY. THIS VIEW IS SUPPORTED BY FINDINGS SHOWING PREFERENTIAL DOWNREGULATION OF PRO-APOPTOTIC GENE EXPRESSION IN THE AFFECTED BRAIN AREAS IN HUMAN ALCOHOLICS. ALTHOUGH FURTHER VERIFICATION IS NEEDED, WE SPECULATE THAT NF-KAPPAB-DRIVEN NEUROINFLAMMATION AND DISRUPTION TO NEUROPLASTICITY PLAY A SIGNIFICANT ROLE IN REGULATING ALCOHOL DEPENDENCE AND COGNITIVE IMPAIRMENT. 2011 8 2493 49 EPIGENETICS AND CHROMATIN REMODELING PLAY A ROLE IN LUNG DISEASE. EPIGENETICS IS DEFINED AS HERITABLE CHANGES THAT AFFECT GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. EPIGENETIC REGULATION OF GENE EXPRESSION IS FACILITATED THROUGH DIFFERENT MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-ASSOCIATED SILENCING BY SMALL NON-CODING RNAS. ALL THESE MECHANISMS ARE CRUCIAL FOR NORMAL DEVELOPMENT, DIFFERENTIATION AND TISSUE-SPECIFIC GENE EXPRESSION. THESE THREE SYSTEMS INTERACT AND STABILIZE ONE ANOTHER AND CAN INITIATE AND SUSTAIN EPIGENETIC SILENCING, THUS DETERMINING HERITABLE CHANGES IN GENE EXPRESSION. HISTONE ACETYLATION REGULATES DIVERSE CELLULAR FUNCTIONS INCLUDING INFLAMMATORY GENE EXPRESSION, DNA REPAIR AND CELL PROLIFERATION. TRANSCRIPTIONAL COACTIVATORS POSSESS INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY AND THIS ACTIVITY DRIVES INFLAMMATORY GENE EXPRESSION. ELEVEN CLASSICAL HISTONE DEACETYLASES (HDACS) ACT TO REGULATE THE EXPRESSION OF DISTINCT SUBSETS OF INFLAMMATORY/IMMUNE GENES. THUS, LOSS OF HDAC ACTIVITY OR THE PRESENCE OF HDAC INHIBITORS CAN FURTHER ENHANCE INFLAMMATORY GENE EXPRESSION BY PRODUCING A GENE-SPECIFIC CHANGE IN HAT ACTIVITY. FOR EXAMPLE, HDAC2 EXPRESSION AND ACTIVITY ARE REDUCED IN LUNG MACROPHAGES, BIOPSY SPECIMENS, AND BLOOD CELLS FROM PATIENTS WITH SEVERE ASTHMA AND SMOKING ASTHMATICS, AS WELL AS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS MAY ACCOUNT, AT LEAST IN PART, FOR THE ENHANCED INFLAMMATION AND REDUCED STEROID RESPONSIVENESS SEEN IN THESE PATIENTS. OTHER PROTEINS, PARTICULARLY TRANSCRIPTION FACTORS, ARE ALSO ACETYLATED AND ARE TARGETS FOR DEACETYLATION BY HDACS AND SIRTUINS, A RELATED FAMILY OF 7 PREDOMINANTLY PROTEIN DEACETYLASES. THUS THE ACETYLATION/DEACETYLATION STATUS OF NF-KAPPAB AND THE GLUCOCORTICOID RECEPTOR CAN ALSO AFFECT THE OVERALL EXPRESSION PATTERN OF INFLAMMATORY GENES AND REGULATE THE INFLAMMATORY RESPONSE. UNDERSTANDING AND TARGETING SPECIFIC ENZYMES INVOLVED IN THIS PROCESS MIGHT LEAD TO NEW THERAPEUTIC AGENTS, PARTICULARLY IN SITUATIONS IN WHICH CURRENT ANTI-INFLAMMATORY THERAPIES ARE SUBOPTIMAL. 2011 9 2036 35 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 10 5710 35 SIRT1 DEFICIENCY IN MICROGLIA CONTRIBUTES TO COGNITIVE DECLINE IN AGING AND NEURODEGENERATION VIA EPIGENETIC REGULATION OF IL-1BETA. AGING IS THE PREDOMINANT RISK FACTOR FOR NEURODEGENERATIVE DISEASES. ONE KEY PHENOTYPE AS THE BRAIN AGES IS AN ABERRANT INNATE IMMUNE RESPONSE CHARACTERIZED BY PROINFLAMMATION. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING AGING-ASSOCIATED PROINFLAMMATION ARE POORLY DEFINED. WHETHER CHRONIC INFLAMMATION PLAYS A CAUSAL ROLE IN COGNITIVE DECLINE IN AGING AND NEURODEGENERATION HAS NOT BEEN ESTABLISHED. HERE WE REPORT A MECHANISTIC LINK BETWEEN CHRONIC INFLAMMATION AND AGING MICROGLIA AND A CAUSAL ROLE OF AGING MICROGLIA IN NEURODEGENERATIVE COGNITIVE DEFICITS. WE SHOWED THAT SIRT1 IS REDUCED WITH THE AGING OF MICROGLIA AND THAT MICROGLIAL SIRT1 DEFICIENCY HAS A CAUSATIVE ROLE IN AGING- OR TAU-MEDIATED MEMORY DEFICITS VIA IL-1BETA UPREGULATION IN MICE. INTERESTINGLY, THE SELECTIVE ACTIVATION OF IL-1BETA TRANSCRIPTION BY SIRT1 DEFICIENCY IS LIKELY MEDIATED THROUGH HYPOMETHYLATING THE SPECIFIC CPG SITES ON IL-1BETA PROXIMAL PROMOTER. IN HUMANS, HYPOMETHYLATION OF IL-1BETA IS STRONGLY ASSOCIATED WITH CHRONOLOGICAL AGE AND WITH ELEVATED IL-1BETA TRANSCRIPTION. OUR FINDINGS REVEAL A NOVEL EPIGENETIC MECHANISM IN AGING MICROGLIA THAT CONTRIBUTES TO COGNITIVE DEFICITS IN AGING AND NEURODEGENERATIVE DISEASES. 2015 11 3961 43 LONG NON-CODING RNAS: THE NEW FRONTIER INTO UNDERSTANDING THE ETIOLOGY OF ALCOHOL USE DISORDER. ALCOHOL USE DISORDER (AUD) IS A COMPLEX, CHRONIC, DEBILITATING CONDITION IMPACTING MILLIONS WORLDWIDE. GENETIC, ENVIRONMENTAL, AND EPIGENETIC FACTORS ARE KNOWN TO CONTRIBUTE TO THE DEVELOPMENT OF AUD. LONG NON-CODING RNAS (LNCRNAS) ARE A CLASS OF REGULATORY RNAS, COMMONLY REFERRED TO AS THE "DARK MATTER" OF THE GENOME, WITH LITTLE TO NO PROTEIN-CODING POTENTIAL. LNCRNAS HAVE BEEN IMPLICATED IN NUMEROUS PROCESSES CRITICAL FOR CELL SURVIVAL, SUGGESTING THAT THEY PLAY IMPORTANT FUNCTIONAL ROLES IN REGULATING DIFFERENT CELL PROCESSES. LNCRNAS WERE ALSO SHOWN TO DISPLAY HIGHER TISSUE SPECIFICITY THAN PROTEIN-CODING GENES AND HAVE A HIGHER ABUNDANCE IN THE BRAIN AND CENTRAL NERVOUS SYSTEM, DEMONSTRATING A POSSIBLE ROLE IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS. INDEED, GENETIC (E.G., GENOME-WIDE ASSOCIATION STUDIES (GWAS)), MOLECULAR (E.G., EXPRESSION QUANTITATIVE TRAIT LOCI (EQTL)) AND EPIGENETIC STUDIES FROM POSTMORTEM BRAIN TISSUES HAVE IDENTIFIED A GROWING LIST OF LNCRNAS ASSOCIATED WITH NEUROPSYCHIATRIC AND SUBSTANCE USE DISORDERS. GIVEN THAT THE EXPRESSION PATTERNS OF LNCRNAS HAVE BEEN ASSOCIATED WITH WIDESPREAD CHANGES IN THE TRANSCRIPTOME, INCLUDING METHYLATION, CHROMATIN ARCHITECTURE, AND ACTIVATION OR SUPPRESSION OF TRANSLATIONAL ACTIVITY, THE REGULATORY NATURE OF LNCRNAS MAY BE UBIQUITOUS AND AN INNATE COMPONENT OF GENE REGULATION. IN THIS REVIEW, WE PRESENT A SYNOPSIS OF THE FUNCTIONAL IMPACT THAT LNCRNAS MAY PLAY IN THE ETIOLOGY OF AUD. WE ALSO DISCUSS THE CLASSIFICATIONS OF LNCRNAS, THEIR KNOWN FUNCTIONAL ROLES, AND THERAPEUTIC ADVANCEMENTS IN THE FIELD OF LNCRNAS TO FURTHER CLARIFY THE FUNCTIONAL RELATIONSHIP BETWEEN LNCRNAS AND AUD. 2022 12 2303 43 EPIGENETIC REGULATION OF CANNABINOID-MEDIATED ATTENUATION OF INFLAMMATION AND ITS IMPACT ON THE USE OF CANNABINOIDS TO TREAT AUTOIMMUNE DISEASES. CHRONIC INFLAMMATION IS CONSIDERED TO BE A SILENT KILLER BECAUSE IT IS THE UNDERLYING CAUSE OF A WIDE RANGE OF CLINICAL DISORDERS, FROM CARDIOVASCULAR TO NEUROLOGICAL DISEASES, AND FROM CANCER TO OBESITY. IN ADDITION, THERE ARE OVER 80 DIFFERENT TYPES OF DEBILITATING AUTOIMMUNE DISEASES FOR WHICH THERE ARE NO CURE. CURRENTLY, THE DRUGS THAT ARE AVAILABLE TO SUPPRESS CHRONIC INFLAMMATION ARE EITHER INEFFECTIVE OR OVERTLY SUPPRESS THE INFLAMMATION, THEREBY CAUSING INCREASED SUSCEPTIBILITY TO INFECTIONS AND CANCER. THUS, THE DEVELOPMENT OF A NEW CLASS OF DRUGS THAT CAN SUPPRESS CHRONIC INFLAMMATION IS IMPERATIVE. CANNABINOIDS ARE A GROUP OF COMPOUNDS PRODUCED IN THE BODY (ENDOCANNABINOIDS) OR FOUND IN CANNABIS (PHYTOCANNABINOIDS) THAT ACT THROUGH CANNABINOID RECEPTORS AND VARIOUS OTHER RECEPTORS EXPRESSED WIDELY IN THE BRAIN AND IMMUNE SYSTEM. IN THE LAST DECADE, CANNABINOIDS HAVE BEEN WELL ESTABLISHED EXPERIMENTALLY TO MEDIATE ANTI-INFLAMMATORY PROPERTIES. RESEARCH HAS SHOWN THAT THEY SUPPRESS INFLAMMATION THROUGH MULTIPLE PATHWAYS, INCLUDING APOPTOSIS AND INDUCING IMMUNOSUPPRESSIVE T REGULATORY CELLS (TREGS) AND MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS). INTERESTINGLY, CANNABINOIDS ALSO MEDIATE EPIGENETIC ALTERATIONS IN GENES THAT REGULATE INFLAMMATION. IN THE CURRENT REVIEW, WE HIGHLIGHT HOW THE EPIGENETIC MODULATIONS CAUSED BY CANNABINOIDS LEAD TO THE SUPPRESSION OF INFLAMMATION AND HELP IDENTIFY NOVEL PATHWAYS THAT CAN BE USED TO TARGET AUTOIMMUNE DISEASES. 2021 13 5581 36 ROLE OF NF-KAPPAB IN AGEING AND AGE-RELATED DISEASES: LESSONS FROM GENETICALLY MODIFIED MOUSE MODELS. AGEING IS A COMPLEX PROCESS, INDUCED BY MULTIFACETED INTERACTION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS. IT IS MANIFESTED BY A DECLINE IN THE PHYSIOLOGICAL FUNCTIONS OF ORGANISMS AND ASSOCIATED TO THE DEVELOPMENT OF AGE-RELATED CHRONIC DISEASES AND CANCER DEVELOPMENT. IT IS CONSIDERED THAT AGEING FOLLOWS A STRICTLY-REGULATED PROGRAM, IN WHICH SOME SIGNALING PATHWAYS CRITICALLY CONTRIBUTE TO THE ESTABLISHMENT AND MAINTENANCE OF THE AGED STATE. CHRONIC INFLAMMATION IS A MAJOR MECHANISM THAT PROMOTES THE BIOLOGICAL AGEING PROCESS AND COMORBIDITY, WITH THE TRANSCRIPTION FACTOR NF-KAPPAB (NUCLEAR FACTOR KAPPA-LIGHT-CHAIN-ENHANCER OF ACTIVATED B CELLS) AS A CRUCIAL MEDIATOR OF INFLAMMATORY RESPONSES. THIS, TOGETHER WITH THE FINDING THAT THE ACTIVATION OR INHIBITION OF NF-KAPPAB CAN INDUCE OR REVERSE RESPECTIVELY THE MAIN FEATURES OF AGED ORGANISMS, HAS BROUGHT IT UNDER CONSIDERATION AS A KEY TRANSCRIPTION FACTOR THAT ACTS AS A DRIVER OF AGEING. IN THIS REVIEW, WE FOCUSED ON THE DATA OBTAINED ENTIRELY THROUGH THE GENERATION OF KNOCKOUT AND TRANSGENIC MOUSE MODELS OF EITHER PROTEIN INVOLVED IN THE NF-KAPPAB SIGNALING PATHWAY THAT HAVE PROVIDED RELEVANT INFORMATION ABOUT THE INTRICATE PROCESSES OR MOLECULAR MECHANISMS THAT CONTROL AGEING. WE HAVE REVIEWED THE RELATIONSHIP OF NF-KAPPAB AND PREMATURE AGEING; THE DEVELOPMENT OF CANCER ASSOCIATED WITH AGEING AND THE IMPLICATION OF NF-KAPPAB ACTIVATION IN THE DEVELOPMENT OF AGE-RELATED DISEASES, SOME OF WHICH GREATLY INCREASE THE RISK OF DEVELOPING CANCER. 2021 14 4969 44 PATHOLOGICAL NEUROINFLAMMATORY CONVERSION OF REACTIVE ASTROCYTES IS INDUCED BY MICROGLIA AND INVOLVES CHROMATIN REMODELING. FOLLOWING BRAIN INJURY OR IN NEURODEGENERATIVE DISEASES, ASTROCYTES BECOME REACTIVE AND MAY SUFFER PATHOLOGICAL REMODELING, FEATURES OF WHICH ARE THE LOSS OF THEIR HOMEOSTATIC FUNCTIONS AND A PRO-INFLAMMATORY GAIN OF FUNCTION THAT FACILITATES NEURODEGENERATION. PHARMACOLOGICAL INTERVENTION TO MODULATE THIS ASTROGLIAL RESPONSE AND NEUROINFLAMMATION IS AN INTERESTING NEW THERAPEUTIC RESEARCH STRATEGY, BUT IT STILL REQUIRES A DEEPER UNDERSTANDING OF THE UNDERLYING CELLULAR AND MOLECULAR MECHANISMS OF THE PHENOMENON. BASED ON THE KNOWN MICROGLIAL-ASTROGLIAL INTERACTION, THE PROMINENT ROLE OF THE NUCLEAR FACTOR KAPPA B (NF-KAPPAB) PATHWAY IN MEDIATING ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION, AND ITS ABILITY TO RECRUIT CHROMATIN-REMODELING ENZYMES, WE FIRST EXPLORED THE MICROGLIAL ROLE IN THE INITIATION OF ASTROGLIAL PRO-INFLAMMATORY CONVERSION AND THEN MONITORED THE PROGRESSION OF EPIGENETIC CHANGES IN THE ASTROCYTIC CHROMATIN. DIFFERENT CONFIGURATIONS OF PRIMARY GLIAL CULTURE WERE USED TO MODULATE MICROGLIA-ASTROCYTE CROSSTALK WHILE INDUCING PRO-INFLAMMATORY GAIN OF FUNCTION BY LIPOPOLYSACCHARIDE (LPS) EXPOSURE. IN VIVO, BRAIN ISCHEMIA BY CORTICAL DEVASCULARIZATION (PIAL DISRUPTION) WAS PERFORMED TO VERIFY THE PRESENCE OF EPIGENETIC MARKS IN REACTIVE ASTROCYTES. OUR RESULTS SHOWED THAT 1) MICROGLIA IS REQUIRED TO INITIATE THE PATHOLOGICAL CONVERSION OF ASTROCYTES BY TRIGGERING THE NF-KAPPAB SIGNALING PATHWAY; 2) THIS INTERACTION IS MEDIATED BY SOLUBLE FACTORS AND INDUCES STABLE ASTROGLIAL PHENOTYPIC CHANGES; 3) THE PATHOLOGICAL CONVERSION PROMOTES CHROMATIN REMODELING WITH STABLE INCREASE IN H3K9K14AC, TEMPORARY INCREASE IN H3K27AC, AND TEMPORARY REDUCTION IN HETEROCHROMATIN MARK H3K9ME3; AND 4) IN VIVO REACTIVE ASTROCYTES SHOW INCREASED H3K27AC MARK IN THE NEUROINFLAMMATORY MILIEU FROM THE ISCHEMIC PENUMBRA. OUR FINDINGS INDICATE THAT ASTROGLIAL PATHOLOGICAL PRO-INFLAMMATORY GAIN OF FUNCTION IS ASSOCIATED WITH PROFOUND CHANGES IN THE CONFIGURATION OF ASTROCYTIC CHROMATIN, WHICH IN TURN ARE INITIATED BY MICROGLIA-DERIVED CUES. THESE RESULTS OPEN A NEW AVENUE IN THE STUDY OF POTENTIAL PHARMACOLOGICAL INTERVENTIONS THAT MODIFY THE INITIATION AND STABILIZATION OF ASTROGLIAL PATHOLOGICAL REMODELING, WHICH WOULD BE USEFUL IN ACUTE AND CHRONIC CNS INJURY. EPIGENETIC CHANGES REPRESENT A PLAUSIBLE PHARMACOLOGICAL TARGET TO INTERFERE WITH THE STABILIZATION OF THE PATHOLOGICAL ASTROGLIAL PHENOTYPE. 2021 15 2499 24 EPIGENETICS AND EXERCISE. EPIGENETICS CAN BE DEFINED AS 'THE STRUCTURAL ADAPTATION OF CHROMOSOMAL REGIONS SO AS TO REGISTER, SIGNAL, OR PERPETUATE ALTERED ACTIVITY STATES.' INCREASED TRANSCRIPTION OF KEY REGULATORY, METABOLIC, AND MYOGENIC GENES IS AN EARLY RESPONSE TO EXERCISE AND IS IMPORTANT IN MEDIATING SUBSEQUENT ADAPTATIONS IN SKELETAL MUSCLE. DNA HYPOMETHYLATION AND HISTONE HYPERACETYLATION ARE EMERGING AS IMPORTANT CRUCIAL EVENTS FOR INCREASED TRANSCRIPTION. THE COMPLEX INTERACTIONS BETWEEN MULTIPLE EPIGENETIC MODIFICATIONS AND THEIR REGULATION BY METABOLIC CHANGES AND SIGNALING EVENTS DURING EXERCISE, WITH IMPLICATIONS FOR ENHANCED UNDERSTANDING OF THE ACUTE AND CHRONIC ADAPTATIONS TO EXERCISE, ARE QUESTIONS FOR FURTHER INVESTIGATION. 2019 16 4620 29 NEURO-IMMUNE DYSFUNCTION DURING BRAIN AGING: NEW INSIGHTS IN MICROGLIAL CELL REGULATION. MICROGLIA, THE RESIDENT IMMUNE CELLS OF THE BRAIN, ARE AT THE CENTER OF COMMUNICATION BETWEEN THE CENTRAL NERVOUS SYSTEM AND IMMUNE SYSTEM. WHILE THESE BRAIN-IMMUNE INTERACTIONS ARE BALANCED IN HEALTHY ADULTHOOD, THE ABILITY TO MAINTAIN HOMEOSTASIS DURING AGING IS IMPAIRED. MICROGLIA DEVELOP A LOSS OF INTEGRATED REGULATORY NETWORKS INCLUDING ABERRANT SIGNALING FROM OTHER BRAIN CELLS, IMMUNE SENSORS, AND EPIGENETIC MODIFIERS. THE LOW-GRADE CHRONIC NEUROINFLAMMATION ASSOCIATED WITH THIS DYSFUNCTIONAL ACTIVITY LIKELY CONTRIBUTES TO COGNITIVE DEFICITS AND SUSCEPTIBILITY TO AGE-RELATED PATHOLOGIES. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS RESPONSIBLE FOR NEURO-IMMUNE DYSREGULATION WITH AGE IS CRUCIAL FOR PROVIDING TARGETED THERAPEUTIC STRATEGIES TO SUPPORT BRAIN REPAIR AND HEALTHY AGING. 2016 17 5561 44 ROLE OF HISTONE DEACETYLASES IN MONOCYTE FUNCTION IN HEALTH AND CHRONIC INFLAMMATORY DISEASES. HISTONE DEACETYLASES (HDACS) ARE A FAMILY OF 18 MEMBERS THAT PARTICIPATE IN THE EPIGENETIC REGULATION OF GENE EXPRESSION. IN ADDITION TO HISTONES, SOME HDACS ALSO DEACETYLATE TRANSCRIPTION FACTORS AND SPECIFIC CYTOPLASMIC PROTEINS.MONOCYTES, AS PART OF THE INNATE IMMUNE SYSTEM, MAINTAIN TISSUE HOMEOSTASIS AND HELP FIGHT INFECTIONS AND CANCER. IN THESE CELLS, HDACS ARE INVOLVED IN MULTIPLE PROCESSES INCLUDING PROLIFERATION, MIGRATION, DIFFERENTIATION, INFLAMMATORY RESPONSE, INFECTIONS, AND TUMORIGENESIS. HERE, A SYSTEMATIC DESCRIPTION OF THE ROLE THAT MOST HDACS PLAY IN THESE FUNCTIONS IS REVIEWED. SPECIFICALLY, SOME HDACS INDUCE A PRO-INFLAMMATORY RESPONSE AND PLAY MAJOR ROLES IN HOST DEFENSE. CONVERSELY, OTHER HDACS REPROGRAM MONOCYTES AND MACROPHAGES TOWARDS AN IMMUNOSUPPRESSIVE PHENOTYPE. THE RIGHT BALANCE BETWEEN BOTH TYPES HELPS MONOCYTES TO RESPOND CORRECTLY TO THE DIFFERENT PHYSIOLOGICAL/PATHOLOGICAL STIMULI. HOWEVER, ABERRANT EXPRESSIONS OR ACTIVITIES OF SPECIFIC HDACS ARE ASSOCIATED WITH AUTOIMMUNE DISEASES ALONG WITH OTHER CHRONIC INFLAMMATORY DISEASES, INFECTIONS, OR CANCER.THIS PAPER CRITICALLY REVIEWS THE INTERESTING AND EXTENSIVE KNOWLEDGE REGARDING THE ROLE OF SOME HDACS IN THESE PATHOLOGIES. IT ALSO SHOWS THAT AS YET, VERY LITTLE PROGRESS HAS BEEN MADE TOWARD THE GOAL OF FINDING EFFECTIVE HDAC-TARGETED THERAPIES. HOWEVER, GIVEN THEIR OBVIOUS POTENTIAL, WE CONCLUDE THAT IT IS WORTH THE EFFORT TO DEVELOP MONOCYTE-SPECIFIC DRUGS THAT SELECTIVELY TARGET HDAC SUBTYPES WITH THE AIM OF FINDING EFFECTIVE TREATMENTS FOR DISEASES IN WHICH OUR INNATE IMMUNE SYSTEM IS INVOLVED. 2021 18 3703 31 INFLAMMATORY SIGNALLING AS MEDIATOR OF EPIGENETIC MODULATION IN TISSUE-SPECIFIC CHRONIC INFLAMMATION. RECENT SUCCESSES OF THERAPEUTIC INTERVENTION IN CHRONIC INFLAMMATORY DISEASES USING EPIGENETIC MODIFIERS SUCH AS HISTONE DEACETYLASE INHIBITORS AND INHIBITORS OF DNA METHYLATION SUGGEST THAT EPIGENETIC REPROGRAMMING PLAYS A ROLE IN THE AETIOLOGY OF THESE DISEASES. THE EPIGENETIC SIGNATURE OF A GIVEN IMMUNE CELL IS REFLECTED IN THE HISTORY OF MODIFICATIONS FROM DIFFERENT SIGNALS THE CELL HAS BEEN SUBJECTED TO DURING DIFFERENTIATION. LIKE OTHER CELLS, DIFFERENTIATING IMMUNE CELLS ARE DEPENDENT ON A COMPLEX COMBINATION OF INTER- AND INTRACELL SIGNALLING AS WELL AS TRANSCRIPTION MACHINERIES TO MODULATE THEIR EPIGENOMES IN ORDER TO MEDIATE DIFFERENTIATION. DESPITE EXTENSIVE RESEARCH INTO THESE PROCESSES, THE LINK BETWEEN CELLULAR SIGNALLING AND EPIGENETIC MODULATION REMAINS POORLY UNDERSTOOD. HERE, WE REVIEW RECENT PROGRESS AND DISCUSS KEY FACTORS DRIVING EPIGENETIC MODULATION IN CHRONIC INFLAMMATION. 2009 19 3772 35 INTERACTION BETWEEN MICRORNA AND DNA METHYLATION IN ATHEROSCLEROSIS. ATHEROSCLEROSIS (AS) IS A CHRONIC INFLAMMATORY DISEASE ACCOMPANIED BY COMPLEX PATHOLOGICAL CHANGES, SUCH AS ENDOTHELIAL DYSFUNCTION, FOAM CELL FORMATION, AND VASCULAR SMOOTH MUSCLE CELL PROLIFERATION. MANY APPROACHES, INCLUDING REGULATING AS-RELATED GENE EXPRESSION IN THE TRANSCRIPTIONAL OR POST-TRANSCRIPTIONAL LEVEL, CONTRIBUTE TO ALLEVIATING AS DEVELOPMENT. THE DNA METHYLATION IS A CRUCIAL EPIGENETIC MODIFICATION IN REGULATING CELL FUNCTION BY SILENCING THE RELATIVE GENE EXPRESSION. THE MICRORNA (MIRNA) IS A TYPE OF NONCODING RNA THAT PLAYS AN IMPORTANT ROLE IN GENE POST-TRANSCRIPTIONAL REGULATION AND DISEASE DEVELOPMENT. THE DNA METHYLATION AND THE MIRNA ARE IMPORTANT EPIGENETIC FACTORS IN AS. HOWEVER, RECENT STUDIES HAVE FOUND A MUTUAL REGULATION BETWEEN THESE TWO FACTORS IN AS DEVELOPMENT. IN THIS STUDY, RECENT INSIGHTS INTO THE ROLES OF MIRNA AND DNA METHYLATION AND THEIR INTERACTION IN THE AS PROGRESSION ARE REVIEWED. 2021 20 4368 55 MIRNA-DEPENDENT CD4(+) T CELL DIFFERENTIATION IN THE PATHOGENESIS OF MULTIPLE SCLEROSIS. MULTIPLE SCLEROSIS (MS) IS CHARACTERIZED BY MULTIFOCAL LESIONS, CHRONIC INFLAMMATORY CONDITION, AND DEGENERATIVE PROCESSES WITHIN THE CENTRAL NERVOUS SYSTEM (CNS) LEADING TO DEMYELINATION. THE MOST IMPORTANT CELLS INVOLVED IN ITS PATHOGENESIS ARE THOSE WHICH ARE CD4(+), PARTICULARLY PROINFLAMMATORY TH1/TH17 AND REGULATORY TREG. SIGNAL CASCADES ASSOCIATED WITH CD4(+) DIFFERENTIATION ARE REGULATED BY MICRORNAS (MIRNAS): SHORT, SINGLE-STRANDED RNAS, RESPONSIBLE FOR NEGATIVE REGULATION OF GENE EXPRESSION AT THE POSTTRANSCRIPTIONAL LEVEL. SEVERAL MIRNAS HAVE BEEN CONSISTENTLY REPORTED AS SHOWING DYSREGULATED EXPRESSION IN MS, AND THEIR EXPRESSION PATTERNS MAY BE ELEVATED OR DECREASED, DEPENDING ON THE FUNCTION OF SPECIFIC MIRNA IN THE IMMUNE SYSTEM. STUDIES IN MS PATIENTS INDICATE THAT, AMONG OTHERS, MIR-141, MIR-200A, MIR-155, MIR-223, AND MIR-326 ARE UPREGULATED, WHILE MIR-15B, MIR-20B, MIR-26A, AND MIR-30A ARE DOWNREGULATED. DYSREGULATION OF THESE MIRNAS MAY CONTRIBUTE TO THE IMBALANCE BETWEEN PRO- AND ANTI-INFLAMMATORY PROCESSES, SINCE THEIR TARGETS ARE ASSOCIATED WITH THE REGULATION OF TH1/TH17 AND TREG CELL DIFFERENTIATION. HIGHLY EXPRESSED MIRNAS CAN IN TURN SUPPRESS TRANSLATION OF KEY TH1/TH17 DIFFERENTIATION INHIBITORS. MIRNA DYSREGULATION MAY RESULT FROM THE IMPACT OF VARIOUS FACTORS AT EACH STAGE OF THEIR BIOGENESIS. IMMATURE MIRNA UNDERGOES MULTISTAGE TRANSCRIPTIONAL AND POSTTRANSCRIPTIONAL MODIFICATIONS; THEREFORE, ANY PROTEIN INVOLVED IN THE PROCESSING OF MIRNAS CAN POTENTIALLY LEAD TO DISTURBANCES IN THEIR EXPRESSION. EPIGENETIC MODIFICATIONS THAT HAVE A DIRECT IMPACT ON MIRNA GENE TRANSCRIPTION MAY ALSO PLAY AN IMPORTANT ROLE. 2021