1 1283 90 DECIPHERING THE EPIGENETIC CODE OF T LYMPHOCYTES. THE MULTIPLE LINEAGES AND DIFFERENTIATION STATES THAT CONSTITUTE THE T-CELL COMPARTMENT ALL DERIVE FROM A COMMON THYMIC PRECURSOR. THESE DISTINCT TRANSCRIPTIONAL STATES ARE MAINTAINED BOTH IN TIME AND AFTER MULTIPLE ROUNDS OF CELL DIVISION BY THE CONCERTED ACTIONS OF A SMALL SET OF LINEAGE-DEFINING TRANSCRIPTION FACTORS THAT ACT IN CONJUNCTION WITH A SUITE OF CHROMATIN-MODIFYING ENZYMES TO ACTIVATE, REPRESS, AND FINE-TUNE GENE EXPRESSION. THESE CHROMATIN MODIFICATIONS COLLECTIVELY PROVIDE AN EPIGENETIC CODE THAT ALLOWS THE STABLE AND HERITABLE MAINTENANCE OF THE T-CELL PHENOTYPE. RECENTLY, IT HAS BECOME APPARENT THAT THE EPIGENETIC CODE REPRESENTS A THERAPEUTIC TARGET FOR A VARIETY OF IMMUNE CELL DISORDERS, INCLUDING LYMPHOMA AND ACUTE AND CHRONIC INFLAMMATORY DISEASES. HERE, WE REVIEW THE RECENT ADVANCES IN EPIGENETIC REGULATION OF GENE EXPRESSION, PARTICULARLY AS IT RELATES TO THE T-CELL DIFFERENTIATION AND FUNCTION. 2014 2 3703 27 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 3 6533 32 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 4 4434 25 MOLECULAR DISSECTION OF CD8(+) T-CELL DYSFUNCTION. CHRONIC VIRAL INFECTIONS AND CANCER OFTEN LEAD TO THE EMERGENCE OF DYSFUNCTIONAL OR 'EXHAUSTED' CD8(+) T CELLS, AND THE RESTORATION OF THEIR FUNCTIONS IS CURRENTLY THE FOCUS OF THERAPEUTIC INTERVENTIONS. IN THIS REVIEW, WE DETAIL RECENT ADVANCES IN THE ANNOTATION OF THE GENE MODULES AND THE EPIGENETIC LANDSCAPE ASSOCIATED WITH T-CELL DYSFUNCTION. TOGETHER WITH ANALYSIS OF SINGLE-CELL TRANSCRIPTOMES, THESE FINDINGS HAVE ENABLED A DEEPER AND MORE PRECISE UNDERSTANDING OF THE TRANSCRIPTIONAL MECHANISMS THAT INDUCE AND MAINTAIN THE DYSFUNCTIONAL STATE AND HIGHLIGHT THE HETEROGENEITY OF CD8(+) T-CELL PHENOTYPES PRESENT IN CHRONICALLY INFLAMED TISSUE. WE DISCUSS THE RELEVANCE OF THESE FINDINGS FOR UNDERSTANDING THE TRANSCRIPTIONAL AND SPATIAL REGULATION OF DYSFUNCTIONAL T CELLS AND FOR THE DESIGN OF THERAPEUTICS. 2017 5 733 29 CANCER EPIGENETICS: LINKING BASIC BIOLOGY TO CLINICAL MEDICINE. CANCER EVOLUTION AT ALL STAGES IS DRIVEN BY BOTH EPIGENETIC ABNORMALITIES AS WELL AS GENETIC ALTERATIONS. DYSREGULATION OF EPIGENETIC CONTROL EVENTS MAY LEAD TO ABNORMAL PATTERNS OF DNA METHYLATION AND CHROMATIN CONFIGURATIONS, BOTH OF WHICH ARE CRITICAL CONTRIBUTORS TO THE PATHOGENESIS OF CANCER. THESE EPIGENETIC ABNORMALITIES ARE SET AND MAINTAINED BY MULTIPLE PROTEIN COMPLEXES AND THE INTERPLAY BETWEEN THEIR INDIVIDUAL COMPONENTS INCLUDING DNA METHYLATION MACHINERY, HISTONE MODIFIERS, PARTICULARLY, POLYCOMB (PCG) PROTEINS, AND CHROMATIN REMODELING PROTEINS. RECENT ADVANCES IN GENOME-WIDE TECHNOLOGY HAVE REVEALED THAT THE INVOLVEMENT OF THESE DYSREGULATED EPIGENETIC COMPONENTS APPEARS TO BE EXTENSIVE. MOREOVER, THERE IS A GROWING CONNECTION BETWEEN EPIGENETIC ABNORMALITIES IN CANCER AND CONCEPTS CONCERNING STEM-LIKE CELL SUBPOPULATIONS AS A DRIVING FORCE FOR CANCER. EMERGING DATA SUGGEST THAT ASPECTS OF THE EPIGENETIC LANDSCAPE INHERENT TO NORMAL EMBRYONIC AND ADULT STEM/PROGENITOR CELLS MAY HELP FOSTER, UNDER THE STRESS OF CHRONIC INFLAMMATION OR ACCUMULATING REACTIVE OXYGEN SPECIES, EVOLUTION OF MALIGNANT SUBPOPULATIONS. FINALLY, UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN INITIATION AND MAINTENANCE OF EPIGENETIC ABNORMALITIES IN ALL TYPES OF CANCER HAS GREAT POTENTIAL FOR TRANSLATIONAL PURPOSES. THIS IS ALREADY EVIDENT FOR EPIGENETIC BIOMARKER DEVELOPMENT, AND FOR PHARMACOLOGICAL TARGETING AIMED AT REVERSING CANCER-SPECIFIC EPIGENETIC ALTERATIONS. 2011 6 2541 26 EPIGENETICS IN KIDNEY DEVELOPMENT AND RENAL DISEASE. THE STUDY OF EPIGENETICS IS INTIMATELY LINKED AND INSEPARABLE FROM DEVELOPMENTAL BIOLOGY. MANY OF THE GENES THAT IMPRINT EPIGENETIC INFORMATION ON CHROMATIN FUNCTION DURING THE SPECIFICATION OF CELL LINEAGES IN THE DEVELOPING EMBRYO. THESE INCLUDE THE HISTONE METHYLTRANSFERASES AND THEIR COFACTORS OF THE POLYCOMB AND TRITHORAX GENE FAMILIES. HOW HISTONE METHYLATION IS ESTABLISHED AND WHAT REGULATES THE TISSUE AND LOCUS SPECIFICITY OF HISTONE METHYLATION IS AN EMERGING AREA OF RESEARCH. THE EMBRYONIC KIDNEY IS USED AS A MODEL TO UNDERSTAND HOW DNA-BINDING PROTEINS CAN SPECIFY CELL LINEAGES AND HOW SUCH PROTEINS INTERACT DIRECTLY WITH THE HISTONE METHYLATION MACHINERY TO GENERATE A UNIQUE EPIGENOME FOR PARTICULAR TISSUES AND CELL TYPES. IN ADULT TISSUES, HISTONE METHYLATION MARKS MUST BE MAINTAINED FOR NORMAL GENE EXPRESSION PATTERNS. IN CHRONIC AND ACUTE RENAL DISEASE, EPIGENETIC MARKS ARE BEING CHARACTERIZED AND CORRELATED WITH THE ESTABLISHMENT OF METABOLIC MEMORY, IN PART TO EXPLAIN THE PERSISTENCE OF PATHOLOGIES EVEN WHEN OPTIMAL TREATMENT MODALITIES ARE USED. THUS, THE STATE OF THE EPIGENOME IN ADULT CELLS MUST BE CONSIDERED WHEN ATTEMPTING TO ALLEVIATE OR ALTER GENE EXPRESSION PATTERNS IN DISEASE. 2015 7 6771 23 [ACQUIRED DISORDERS AND EPIGENETICS]. EPIGENETIC MODIFICATIONS, INVOLVING DNA METHYLATION AND HISTONE MODIFICATIONS, ARE MAINTAINED UPON SOMATIC CELL REPLICATION, AND ARE FUNDAMENTAL MECHANISMS FOR CELLULAR MEMORY. DNA METHYLATION OF PROMOTER CPG ISLANDS OF TUMOR-SUPPRESSOR GENES CAN SILENCE THEIR DOWNSTREAM GENES, AND CAN BE CAUSALLY INVOLVED IN CANCER DEVELOPMENT AND PROGRESSION. SINCE THIS EFFECT IS THE SAME WITH THAT OF INACTIVATING MUTATIONS, THE NATURES OF DNA METHYLATION WERE ONCE CONSIDERED TO BE SIMILAR TO MUTATIONS. HOWEVER, RECENTLY, IT WAS REVEALED THAT A LARGE NUMBER OF EPIGENETIC ALTERATIONS ARE PRESENT IN A SINGLE CANCER CELL, THAT A LARGE NUMBER OF CELLS HAVE AN EPIGENETIC ALTERATION OF A SPECIFIC GENE IN NON-CANCEROUS, THUS POLYCLONAL, TISSUES, THAT GENE SPECIFICITY IN METHYLATION INDUCTION IS PRESENT ACCORDING TO TISSUE TYPES AND INDUCERS, AND THAT CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN METHYLATION INDUCTION. THESE FACTS SUGGEST THAT EPIGENETIC ALTERATIONS OF KEY GENES INVOLVED IN ACQUIRED CHRONIC DISORDERS CAN BE PRESENT IN A SIGNIFICANT FRACTION OF CELLS IN A TISSUE, AND THUS CAN IMPAIR THE FUNCTION OF THE TISSUE. ASSOCIATIONS BETWEEN EPIGENETIC ALTERATIONS AND BEHAVIOR, MEMORY, MENTAL DISORDERS, NEUROLOGICAL DISORDERS, METABOLIC DISORDERS, ALLERGY, AUTOIMMUNE DISORDERS, AND OTHER DISORDERS HAVE BEEN REPORTED. FURTHER RESEARCH IN THE FIELD IS NECESSARY TO CLARIFY THE CAUSAL ROLES OF THESE EPIGENETIC ALTERATIONS IN DISEASE DEVELOPMENT, AND TO APPLY THE FINDINGS TO NEW STRATEGIES OF DISEASE PREVENTION, DIAGNOSIS, AND TREATMENT. 2010 8 2070 26 EPIGENETIC CONTROL OF SKIN IMMUNITY. EPIGENETICS HAS BEEN WELL UNDERSTOOD FOR ITS ROLE IN CELL DEVELOPMENT; HOWEVER, IT IS NOW KNOWN TO REGULATE MANY PROCESSES INVOLVED IN IMMUNE CELL ACTIVATION IN A VARIETY OF CELLS. THE SKIN MAINTAINS HOMEOSTASIS VIA CROSSTALK BETWEEN IMMUNE AND NON-IMMUNE CELLS. DISRUPTION OF NORMAL EPIGENETIC REGULATION IN THESE CELLS MAY ALTER THE TRANSCRIPTION OF IMMUNE-REGULATORY FACTORS AND AFFECT THE IMMUNOLOGICAL BALANCE IN THE SKIN. THIS REVIEW SUMMARIZES RECENT EVIDENCE FOR THE EPIGENETIC REGULATION OF SKIN IMMUNITY. MUCH OF WHAT IS KNOWN ABOUT EPIGENETIC INVOLVEMENT IN SKIN IMMUNITY IS ASSOCIATED WITH DNA METHYLATION. THIS REVIEW FOCUSES ON EPIGENETIC REGULATION OF HISTONE MODIFICATION AND CHROMATIN REMODELING AND DESCRIBES THEIR ROLE IN THE TRANSCRIPTIONAL REGULATION OF IMMUNE-REGULATORY FACTORS. WHILE MUCH IS STILL UNKNOWN REGARDING THE REGULATION OF SKIN IMMUNITY VIA HISTONE MODIFICATION OR CHROMATIN REMODELING, THESE PROCESSES MAY UNDERLIE THE PATHOGENESIS OF CHRONIC CUTANEOUS IMMUNE DISORDERS. 2023 9 2338 29 EPIGENETIC REGULATION OF INFLAMMATORY SIGNALING AND INFLAMMATION-INDUCED CANCER. EPIGENETICS COMPRISE A DIVERSE ARRAY OF REVERSIBLE AND DYNAMIC MODIFICATIONS TO THE CELL'S GENOME WITHOUT IMPLICATING ANY DNA SEQUENCE ALTERATIONS. BOTH THE EXTERNAL ENVIRONMENT SURROUNDING THE ORGANISM, AS WELL AS THE INTERNAL MICROENVIRONMENT OF CELLS AND TISSUES, CONTRIBUTE TO THESE EPIGENETIC PROCESSES THAT PLAY CRITICAL ROLES IN CELL FATE SPECIFICATION AND ORGANISMAL DEVELOPMENT. ON THE OTHER HAND, DYSREGULATION OF EPIGENETIC ACTIVITIES CAN INITIATE AND SUSTAIN CARCINOGENESIS, WHICH IS OFTEN AUGMENTED BY INFLAMMATION. CHRONIC INFLAMMATION, ONE OF THE MAJOR HALLMARKS OF CANCER, STEMS FROM PROINFLAMMATORY CYTOKINES THAT ARE SECRETED BY TUMOR AND TUMOR-ASSOCIATED CELLS IN THE TUMOR MICROENVIRONMENT. AT THE SAME TIME, INFLAMMATORY SIGNALING CAN ESTABLISH POSITIVE AND NEGATIVE FEEDBACK CIRCUITS WITH CHROMATIN TO MODULATE CHANGES IN THE GLOBAL EPIGENETIC LANDSCAPE. IN THIS REVIEW, WE PROVIDE AN IN-DEPTH DISCUSSION OF THE INTERCONNECTED CROSSTALK BETWEEN EPIGENETICS AND INFLAMMATION, SPECIFICALLY HOW EPIGENETIC MECHANISMS AT DIFFERENT HIERARCHICAL LEVELS OF THE GENOME CONTROL INFLAMMATORY GENE TRANSCRIPTION, WHICH IN TURN ENACT CHANGES WITHIN THE CELL'S EPIGENOMIC PROFILE, ESPECIALLY IN THE CONTEXT OF INFLAMMATION-INDUCED CANCER. 2022 10 3799 22 INTERPLAY BETWEEN INFLAMMATION AND EPIGENETIC CHANGES IN CANCER. IMMUNE RESPONSES CAN SUPPRESS TUMORIGENESIS, BUT ALSO CONTRIBUTE TO CANCER INITIATION AND PROGRESSION SUGGESTING A COMPLEX INTERACTION BETWEEN THE IMMUNE SYSTEM AND CANCER. EPIGENETIC ALTERATIONS, WHICH ARE HERITABLE CHANGES IN GENE EXPRESSION WITHOUT CHANGES TO THE DNA SEQUENCE, ALSO PLAY A ROLE IN CARCINOGENESIS THROUGH SILENCING EXPRESSION OF TUMOR SUPPRESSOR GENES AND ACTIVATING ONCOGENIC SIGNALING. INTERESTINGLY, EPITHELIAL CELLS AT SITES OF CHRONIC INFLAMMATION UNDERGO DNA METHYLATION ALTERATIONS THAT ARE SIMILAR TO THOSE PRESENT IN CANCER CELLS, SUGGESTING THAT INFLAMMATION MAY INITIATE CANCER-SPECIFIC EPIGENETIC CHANGES IN EPITHELIAL CELLS. FURTHERMORE, EPIGENETIC CHANGES OCCUR DURING IMMUNE CELL DIFFERENTIATION AND PARTICIPATE IN REGULATING THE IMMUNE RESPONSE, INCLUDING THE REGULATION OF INFLAMMATORY CYTOKINES. CANCER CELLS UTILIZE EPIGENETIC SILENCING OF IMMUNE-RELATED GENES TO EVADE THE IMMUNE RESPONSE. THIS CHAPTER WILL DETAIL THE INTERACTIONS BETWEEN INFLAMMATION AND EPIGENETICS IN TUMOR INITIATION, PROMOTION, AND IMMUNE EVASION AND HOW THESE CONNECTIONS ARE BEING LEVERAGED IN CANCER PREVENTION AND TREATMENT. 2016 11 5550 32 ROLE OF EPIGENETICS IN INFLAMMATION-ASSOCIATED DISEASES. THERE IS CONSIDERABLE EVIDENCE SUGGESTING THAT EPIGENETIC MECHANISMS MAY MEDIATE DEVELOPMENT OF CHRONIC INFLAMMATION BY MODULATING THE EXPRESSION OF PRO-INFLAMMATORY CYTOKINE TNF-ALPHA, INTERLEUKINS, TUMOR SUPPRESSOR GENES, ONCOGENES AND AUTOCRINE AND PARACRINE ACTIVATION OF THE TRANSCRIPTION FACTOR NF-KAPPAB. THESE MOLECULES ARE CONSTITUTIVELY PRODUCED BY A VARIETY OF CELLS UNDER CHRONIC INFLAMMATORY CONDITIONS, WHICH IN TURN LEADS TO THE DEVELOPMENT OF MAJOR DISEASES SUCH AS AUTOIMMUNE DISORDERS, CHRONIC OBSTRUCTIVE PULMONARY DISEASES, NEURODEGENERATIVE DISEASES AND CANCER. DISTINCT OR GLOBAL CHANGES IN THE EPIGENETIC LANDSCAPE ARE HALLMARKS OF CHRONIC INFLAMMATION DRIVEN DISEASES. EPIGENETICS INCLUDE CHANGES TO DISTINCT MARKERS ON THE GENOME AND ASSOCIATED CELLULAR TRANSCRIPTIONAL MACHINERY THAT ARE COPIED DURING CELL DIVISION (MITOSIS AND MEIOSIS). THESE CHANGES APPEAR FOR A SHORT SPAN OF TIME AND THEY NECESSARILY DO NOT MAKE PERMANENT CHANGES TO THE PRIMARY DNA SEQUENCE ITSELF. HOWEVER, THE MOST FREQUENTLY OBSERVED EPIGENETIC CHANGES INCLUDE ABERRANT DNA METHYLATION, AND HISTONE ACETYLATION AND DEACETYLATION. IN THIS CHAPTER, WE FOCUS ON PRO-INFLAMMATORY MOLECULES THAT ARE REGULATED BY ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS ARGININE AND LYSINE METHYL TRANSFERASES, DNA METHYLTRANSFERASE, HISTONE ACETYLTRANSFERASES AND HISTONE DEACETYLASES AND THEIR ROLE IN INFLAMMATION DRIVEN DISEASES. AGENTS THAT MODULATE OR INHIBIT THESE EPIGENETIC MODIFICATIONS, SUCH AS HAT OR HDAC INHIBITORS HAVE SHOWN GREAT POTENTIAL IN INHIBITING THE PROGRESSION OF THESE DISEASES. GIVEN THE PLASTICITY OF THESE EPIGENETIC CHANGES AND THEIR READINESS TO RESPOND TO INTERVENTION BY SMALL MOLECULE INHIBITORS, THERE IS A TREMENDOUS POTENTIAL FOR THE DEVELOPMENT OF NOVEL THERAPEUTICS THAT WILL SERVE AS DIRECT OR ADJUVANT THERAPEUTIC COMPOUNDS IN THE TREATMENT OF THESE DISEASES. 2013 12 2056 29 EPIGENETIC CONTROL OF CD8(+) T CELL DIFFERENTIATION. UPON STIMULATION, SMALL NUMBERS OF NAIVE CD8(+) T CELLS PROLIFERATE AND DIFFERENTIATE INTO A VARIETY OF MEMORY AND EFFECTOR CELL TYPES. CD8(+) T CELLS CAN PERSIST FOR YEARS AND KILL TUMOUR CELLS AND VIRALLY INFECTED CELLS. THE FUNCTIONAL AND PHENOTYPIC CHANGES THAT OCCUR DURING CD8(+) T CELL DIFFERENTIATION ARE WELL CHARACTERIZED, BUT THE EPIGENETIC STATES THAT UNDERLIE THESE CHANGES ARE INCOMPLETELY UNDERSTOOD. HERE, WE REVIEW THE EPIGENETIC PROCESSES THAT DIRECT CD8(+) T CELL DIFFERENTIATION AND FUNCTION. WE FOCUS ON EPIGENETIC MODIFICATION OF DNA AND ASSOCIATED HISTONES AT GENES AND THEIR REGULATORY ELEMENTS. WE ALSO DESCRIBE STRUCTURAL CHANGES IN CHROMATIN ORGANIZATION THAT AFFECT GENE EXPRESSION. FINALLY, WE EXAMINE THE TRANSLATIONAL POTENTIAL OF EPIGENETIC INTERVENTIONS TO IMPROVE CD8(+) T CELL FUNCTION IN INDIVIDUALS WITH CHRONIC INFECTIONS AND CANCER. 2018 13 5410 28 REGULATION OF ADAPTIVE IMMUNE CELLS BY SIRTUINS. IT IS NOW WELL-ESTABLISHED THAT THE PATHWAYS THAT CONTROL LYMPHOCYTE METABOLISM AND FUNCTION ARE INTIMATELY LINKED, AND CHANGES IN LYMPHOCYTE METABOLISM CAN INFLUENCE AND DIRECT CELLULAR FUNCTION. INTERESTINGLY, A NUMBER OF RECENT ADVANCES INDICATE THAT LYMPHOCYTE IDENTITY AND METABOLISM IS PARTIALLY CONTROLLED VIA EPIGENETIC REGULATION. EPIGENETIC MECHANISMS, SUCH AS CHANGES IN DNA METHYLATION OR HISTONE ACETYLATION, HAVE BEEN FOUND TO ALTER IMMUNE FUNCTION AND PLAY A ROLE IN NUMEROUS CHRONIC DISEASE STATES. THERE ARE SEVERAL ENZYMES THAT CAN MEDIATE EPIGENETIC CHANGES; OF PARTICULAR INTEREST ARE SIRTUINS, PROTEIN DEACETYLASES THAT MEDIATE ADAPTIVE RESPONSES TO A VARIETY OF STRESSES (INCLUDING CALORIE RESTRICTION AND METABOLIC STRESS) AND ARE NOW UNDERSTOOD TO PLAY A SIGNIFICANT ROLE IN IMMUNITY. THIS REVIEW WILL FOCUS ON RECENT ADVANCES IN THE UNDERSTANDING OF HOW SIRTUINS AFFECT THE ADAPTIVE IMMUNE SYSTEM. THESE PATHWAYS ARE OF SIGNIFICANT INTEREST AS THERAPEUTIC TARGETS FOR THE TREATMENT OF AUTOIMMUNITY, CANCER, AND TRANSPLANT TOLERANCE. 2019 14 2036 19 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 15 1232 31 CROSSTALK BETWEEN INFLAMMATORY SIGNALING AND METHYLATION IN CANCER. INFLAMMATION IS AN INTRICATE IMMUNE RESPONSE AGAINST INFECTION AND TISSUE DAMAGE. WHILE THE INITIAL IMMUNE RESPONSE IS IMPORTANT FOR PREVENTING TUMORIGENESIS, CHRONIC INFLAMMATION IS IMPLICATED IN CANCER PATHOGENESIS. IT HAS BEEN LINKED TO VARIOUS STAGES OF TUMOR DEVELOPMENT INCLUDING TRANSFORMATION, PROLIFERATION, ANGIOGENESIS, AND METASTASIS. IMMUNE CELLS, THROUGH THE PRODUCTION OF INFLAMMATORY MEDIATORS SUCH AS CYTOKINES, CHEMOKINES, TRANSFORMING GROWTH FACTORS, AND ADHESION MOLECULES CONTRIBUTE TO THE SURVIVAL, GROWTH, AND PROGRESSION OF THE TUMOR IN ITS MICROENVIRONMENT. THE ABERRANT EXPRESSION AND SECRETION OF PRO-INFLAMMATORY AND GROWTH FACTORS BY THE TUMOR CELLS RESULT IN THE RECRUITMENT OF IMMUNE CELLS, THUS CREATING A MUTUAL CROSSTALK. THE RECIPROCAL SIGNALING BETWEEN THE TUMOR CELLS AND THE IMMUNE CELLS CREATES AND MAINTAINS A SUCCESSFUL TUMOR NICHE. MANY INFLAMMATORY FACTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. IN PARTICULAR, DNA AND HISTONE METHYLATION ARE CRUCIAL FORMS OF TRANSCRIPTIONAL REGULATION AND ABERRANT METHYLATION HAS BEEN ASSOCIATED WITH DEREGULATED GENE EXPRESSION IN ONCOGENESIS. SUCH DEREGULATIONS HAVE BEEN REPORTED IN BOTH SOLID TUMORS AND HEMATOLOGICAL MALIGNANCIES. WITH TECHNOLOGICAL ADVANCEMENTS TO STUDY GENOME-WIDE EPIGENETIC LANDSCAPES, IT IS NOW POSSIBLE TO IDENTIFY MOLECULAR MECHANISMS UNDERLYING ALTERED INFLAMMATORY PROFILES IN CANCER. IN THIS REVIEW, WE DISCUSS THE ROLE OF DNA AND HISTONE METHYLATION IN REGULATION OF INFLAMMATORY PATHWAYS IN HUMAN CANCERS AND REVIEW THE MERITS AND CHALLENGES OF TARGETING INFLAMMATORY MEDIATORS AS WELL AS EPIGENETIC REGULATORS IN CANCER. 2021 16 2399 19 EPIGENETIC REPROGRAMMING OF HOST GENES IN VIRAL AND MICROBIAL PATHOGENESIS. ONE OF THE KEY QUESTIONS IN THE STUDY OF MAMMALIAN GENE REGULATION IS HOW EPIGENETIC METHYLATION PATTERNS ON HISTONES AND DNA ARE INITIATED AND ESTABLISHED. THESE STABLE, HERITABLE, COVALENT MODIFICATIONS ARE LARGELY ASSOCIATED WITH THE REPRESSION OR SILENCING OF GENE TRANSCRIPTION, AND WHEN DEREGULATED CAN BE INVOLVED IN THE DEVELOPMENT OF HUMAN DISEASES SUCH AS CANCER. THIS ARTICLE REVIEWS EXAMPLES OF VIRUSES AND BACTERIA KNOWN OR THOUGHT TO INDUCE EPIGENETIC CHANGES IN HOST CELLS, AND HOW THIS MIGHT CONTRIBUTE TO DISEASE. THE HERITABLE NATURE OF THESE PROCESSES IN GENE REGULATION SUGGESTS THAT THEY COULD PLAY IMPORTANT ROLES IN CHRONIC DISEASES ASSOCIATED WITH MICROBIAL PERSISTENCE; THEY MIGHT ALSO EXPLAIN SO-CALLED 'HIT-AND-RUN' PHENOMENA IN INFECTIOUS DISEASE PATHOGENESIS. 2010 17 2033 26 EPIGENETIC CHANGES IN SOLID AND HEMATOPOIETIC TUMORS. THERE ARE THREE CONNECTED MOLECULAR MECHANISMS OF EPIGENETIC CELLULAR MEMORY IN MAMMALIAN CELLS: DNA METHYLATION, HISTONE MODIFICATIONS, AND RNA INTERFERENCE. THE FIRST TWO HAVE NOW BEEN FIRMLY LINKED TO NEOPLASTIC TRANSFORMATION. HYPERMETHYLATION OF CPG-RICH PROMOTERS TRIGGERS LOCAL HISTONE CODE MODIFICATIONS RESULTING IN A CELLULAR CAMOUFLAGE MECHANISM THAT SEQUESTERS GENE PROMOTERS AWAY FROM TRANSCRIPTION FACTORS AND RESULTS IN STABLE SILENCING. THIS NORMALLY RESTRICTED MECHANISM IS UBIQUITOUSLY USED IN CANCER TO SILENCE HUNDREDS OF GENES, AMONG WHICH SOME CRITICALLY CONTRIBUTE TO THE NEOPLASTIC PHENOTYPE. VIRTUALLY EVERY PATHWAY IMPORTANT TO CANCER FORMATION IS AFFECTED BY THIS PROCESS. METHYLATION PROFILING OF HUMAN CANCERS REVEALS TISSUE-SPECIFIC EPIGENETIC SIGNATURES, AS WELL AS TUMOR-SPECIFIC SIGNATURES, REFLECTING IN PARTICULAR THE PRESENCE OF EPIGENETIC INSTABILITY IN A SUBSET OF CANCERS AFFECTED BY THE CPG ISLAND METHYLATOR PHENOTYPE. GENERALLY, METHYLATION PATTERNS CAN BE TRACED TO A TISSUE-SPECIFIC, PROLIFERATION-DEPENDENT ACCUMULATION OF ABERRANT PROMOTER METHYLATION IN AGING TISSUES, A PROCESS THAT CAN BE ACCELERATED BY CHRONIC INFLAMMATION AND LESS WELL-DEFINED MECHANISMS INCLUDING, POSSIBLY, DIET AND GENETIC PREDISPOSITION. THE EPIGENETIC MACHINERY CAN ALSO BE ALTERED IN CANCER BY SPECIFIC LESIONS IN EPIGENETIC EFFECTOR GENES, OR BY ABERRANT RECRUITMENT OF THESE GENES BY MUTANT TRANSCRIPTION FACTORS AND COACTIVATORS. EPIGENETIC PATTERNS ARE PROVING CLINICALLY USEFUL IN HUMAN ONCOLOGY VIA RISK ASSESSMENT, EARLY DETECTION, AND PROGNOSTIC CLASSIFICATION. PHARMACOLOGIC MANIPULATION OF THESE PATTERNS-EPIGENETIC THERAPY-IS ALSO POISED TO CHANGE THE WAY WE TREAT CANCER IN THE CLINIC. 2005 18 4200 33 METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS: REGULATION AND DEFECTS IN HEALTH AND IN INFLAMMATORY DISEASES. THE IMMUNE SYSTEM PROTECTS FROM INFECTIONS AND CANCER THROUGH COMPLEX CELLULAR NETWORKS. FOR THIS PURPOSE, IMMUNE CELLS REQUIRE WELL-DEVELOPED MECHANISMS OF ENERGY GENERATION. HOWEVER, THE IMMUNE SYSTEM ITSELF CAN ALSO CAUSE DISEASES WHEN DEFECTIVE REGULATION RESULTS IN THE EMERGENCE OF AUTOREACTIVE LYMPHOCYTES. RECENT STUDIES PROVIDE INSIGHTS INTO HOW DIFFERENTIAL PATTERNS OF IMMUNE CELL RESPONSES ARE ASSOCIATED WITH SELECTIVE METABOLIC PATHWAYS. THIS REVIEW WILL EXAMINE THE CHANGING METABOLIC REQUIREMENTS OF TH17 CELLS AND OF B CELLS AT DIFFERENT STAGES OF THEIR DEVELOPMENT AND ACTIVATION. BOTH CELLS PROVIDE PROTECTION BUT CAN ALSO MEDIATE DISEASES THROUGH THE PRODUCTION OF AUTOANTIBODIES AND THE PRODUCTION OF PROINFLAMMATORY MEDIATORS. IN HEALTH, B CELLS PRODUCE ANTIBODIES AND CYTOKINES AND PRESENT ANTIGENS TO T CELLS TO MOUNT SPECIFIC IMMUNITY. TH17 CELLS, ON THE OTHER HAND, PROVIDE PROTECTION AGAINST EXTRA CELLULAR PATHOGENS AT MUCOSAL SURFACES BUT CAN ALSO DRIVE CHRONIC INFLAMMATION. THE LATTER CELLS CAN ALSO PROMOTE THE DIFFERENTIATION OF B CELLS TO PLASMA CELLS TO PRODUCE MORE AUTOANTIBODIES. METABOLISM-REGULATED CHECKPOINTS AT DIFFERENT STAGES OF THEIR DEVELOPMENT ENSURE THE THAT SELF-REACTIVE B CELLS CLONES AND NEEDLESS PRODUCTION OF INTERLEUKIN (IL-)17 ARE LIMITED. THE METABOLIC REGULATION OF THE TWO CELL TYPES HAS SOME SIMILARITIES, E.G. THE UTILITY OF HYPOXIA INDUCED FACTOR (HIF)1ALPHA DURING LOW OXYGEN TENSION, TO PREVENT AUTOIMMUNITY AND REGULATE INFLAMMATION. THERE ARE ALSO CLEAR DIFFERENCES, AS TH17 CELLS ONLY ARE VULNERABLE TO THE LACK OF CERTAIN AMINO ACIDS. B CELLS, UNLIKE TH17 CELLS, ARE ALSO DEPENDENT OF MECHANISTIC TARGET OF RAPAMYCIN 2 (MTORC2) TO FUNCTION. SIGNIFICANT KNOWLEDGE HAS RECENTLY BEEN GAINED, PARTICULARLY ON TH17 CELLS, ON HOW METABOLISM REGULATES THESE CELLS THROUGH INFLUENCING THEIR EPIGENOME. METABOLIC DYSREGULATION OF TH17 CELLS AND B CELLS CAN LEAD TO CHRONIC INFLAMMATION. DISEASE ASSOCIATED ALTERATIONS IN THE GENOME CAN, IN ADDITION, CAUSE DYSREGULATION TO METABOLISM AND, THEREBY, RESULT IN EPIGENETIC ALTERATIONS IN THESE CELLS. RECENT STUDIES HIGHLIGHT HOW PATHOLOGY CAN RESULT FROM THE COOPERATION BETWEEN THE TWO CELL TYPES BUT ONLY FEW HAVE SO FAR ADDRESSED THE KEY METABOLIC ALTERATIONS IN SUCH SETTINGS. KNOWLEDGE OF THE IMPACT OF METABOLIC DYSFUNCTION ON CHRONIC INFLAMMATION AND PATHOLOGY CAN REVEAL NOVEL THERAPEUTIC TARGETS TO TREAT SUCH DISEASES. 2022 19 6809 28 [EPIGENETICS IN INFLAMMATORY SYSTEMIC DISEASES]. IN ADDITION TO ANALYSIS OF THE GENETIC CODE, IN RECENT YEARS MORE AND MORE STUDIES HAVE CONCENTRATED ON CHANGES IN THE EPIGENETIC CODE. EPIGENETIC MECHANISMS DETERMINE WHICH GENES IN A CELL ARE TRANSCRIBED AND THUS FORM THE PHENOTYPE OF A CELL. THE EPIGENETIC CODE CAN BE CHANGED BY ENVIRONMENTAL INFLUENCES, WHICH ALLOWS CELLS TO ADAPT TO LONGSTANDING CHANGES IN THE ENVIRONMENT. THEREFORE, IT IS FEASIBLE TO ASSUME THAT EPIGENETIC CHANGES ARE THE MOLECULAR BASIS FOR LONG-TERM EFFECTS OF THE ENVIRONMENT ON DISEASE DEVELOPMENT. IN PARTICULAR IN TUMORS AND CHRONIC INFLAMMATORY DISEASES EPIGENETIC CHANGES WERE FOUND TO CORRELATE WITH DISEASE SEVERITY AND PROGRESSION. KNOWLEDGE ABOUT THESE EPIGENETIC CHANGES MIGHT HELP THAT EPIGENETIC MODIFICATIONS CAN BE USED IN THE FUTURE AS BIOMARKERS, PROGNOSTIC FACTORS AND THERAPEUTIC TARGETS. 2014 20 4228 24 METHYLATION OF INFLAMMATORY CELLS IN LUNG DISEASES. THIS CHAPTER OVERVIEWS ROLES OF DNA METHYLATION IN INFLAMMATORY CELL BIOLOGY WITH THE FOCUSES ON LYMPHOCYTES AND MACROPHAGES/MONOCYTES IN LUNG DISEASES, ALTHOUGH THE MOLECULAR MECHANISMS BY WHICH TARGET GENES ARE METHYLATED AND REGULATED IN LUNG DISEASES REMAIN UNCLEAR. MOST OF EPIGENETIC STUDIES ON DNA METHYLATION OF TARGET GENES IN LUNG DISEASES MAINLY DEMONSTRATED THE CORRELATION OF DNA METHYLATION OF TARGET GENES WITH THE LEVELS OF OTHER CORRESPONDING FACTORS, WITH THE SPECIFICITY OF CLINICAL PHENOMES, AND WITH THE SEVERITY OF LUNG DISEASES. THERE IS AN URGENT NEED TO IDENTIFY AND VALIDATE THE SPECIFICITY AND REGULATORY MECHANISMS OF INFLAMMATORY CELL EPIGENETICS IN DEPTH. THE EPIGENETIC HETEROGENEITY AMONG DIFFERENT SUBSETS OF T CELLS AND AMONG PROMOTERS OR NON-PROMOTERS OF TARGET GENES SHOULD BE FURTHERMORE CLARIFIED IN ACUTE OR CHRONIC LUNG DISEASES AND CANCERS. THE HYPER/HYPO-METHYLATION AND MODIFICATIONS OF CHROMOSOL AND EXTRACHROMOSOMAL DNA MAY RESULT IN ALTERNATIONS IN PROTEINS WITHIN INFLAMMATORY CELLS, WHICH CAN BE IDENTIFIED AS DISEASE-SPECIFIC BIOMARKERS AND THERAPEUTIC TARGETS. 2020