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CHAPTER 12 DEFINITION AND OVERVIEW

EPIGENETICS Epigenetics is defined as a heritable change in phenotype without a
change in genotype. Although epigenetic mechanisms vary, this chap-
ter focuses on the most common mechanism: chromatin. Changes in
chromatin/epigenetics accompany many steps in transcription, rep-
Bradley R. Cairns lication, and recombination. However, the aspects of highest interest
and relevance involve examples where epigenetic factors and enzymes
drive differentiation decisions, and where misregulation/mutation of
SUMMARY these factors drives pathologies, such as hematologic malignancies. This
decision making must be precise, as differentiation along the lymphoid
and myeloid lineages involves the regulated generation of multiple cell
Epigenetics involves a heritable change in phenotype without a change in types in temporal order and proper proportion. Decisions are arrived
genotype–with the inheritance of particular chromatin and transcription through collaboration among signaling systems, transcription factors,
states often underlying the mechanism. Chromatin regulates gene expression and chromatin regulators-which together regulate the key genes gov-
by controlling the density and positioning of nucleosomes, and by the use of erning self-renewal, differentiation, and survival. This chapter focuses
histone- and DNA-modifying enzymes. Chromatin and transcription factors on chromatin factors with central roles in these processes: ATP-
drive proper differentiation decisions through their coregulation of key factors dependent remodelers, DNA methylation (DNAme)/demethylation
in development and proliferation. Of particular interest to hematologists are enzymes, and histone modification enzymes. As a complete treatment is
instances when misregulation/mutation of chromatin factors drives hema- beyond the scope of this chapter, the focus here will be conceptual, with
tologic malignancies and myeloproliferative disorders. Here, fusion proteins particular examples provided to create a framework for understanding
that involve the mistargeting of chromatin regulators have been known for the many instances where chromatin factors influence decision-making.
decades. More recently, high-throughput sequencing and other genomics Beyond their roles in normal blood cell development, misregula-
approaches have revealed mutations in many types of chromatin regulators tion of chromatin factors is now known to be common in hematologic
malignancies. Indeed, high-throughput whole-genome and/or exome
in hematologic malignancies, including mutations in chromatin remodelers, sequencing of leukemias and lymphomas has revealed mutations in
DNA methylation regulators, histone modification enzymes, and metabolic many types of chromatin regulators, including mutations in chromatin
enzymes affecting epigenetic cofactors. Overall, these studies reveal a con- remodelers, DNA methyltransferases (DNMT), and histone modifica-
sistent theme: epigenetic and genetic mutations confer both variation and tion enzymes, as well as revealing fusion proteins that involve chroma-
plasticity to the transcriptome, and when combined with selection, arrive tin regulators. In certain instances, modeling in the mouse supports
1
at transcriptomes that promote proliferation, survival, and adaptability. This these epigenetic mutations as the main drivers of the cancer phenotype.
chapter addresses these mechanistic principles of chromatin, and their mis- In other instances, epigenetic mutations cooperate with (and likely
regulation in hematologic malignancies, as well as emerging therapeutic enable) additional genetic mutations, which cooperate to impact prolif-
approaches. eration, survival, and plasticity, which can enable both cancer progres-
sion and therapy resistance. However, as many chromatin regulators are
enzymes, they may be more targetable than mutations in DNA bind-
ing transcription factors, providing new therapeutic approaches. This
2
chapter expands on these concepts, addressing the mechanistic basis
of chromatin misregulation in hematologic malignancies, as well as
emerging therapeutic approaches.
Acronyms and Abbreviations: AF, ALL1-fused gene; ALL, acute lymphocytic leu-
kemia; AML, acute myeloid leukemia; BAF, BRG/BAF-associated factors; BCL, B-cell CHROMATIN REMODELING AND
lymphoma family of regulator proteins that regulate cell death; BET, bromo and DNA ACCESS
extraterminal; CHD, chromodomain remodeler; CMML, chronic myelomonocytic leu-
kemia; DNAme, DNA methylation; DNMT, DNA methyltransferase; DOT1, a histone H3 CHROMATIN REGULATES TRANSCRIPTION
methyltransferase; EGR1, early growth response protein 1; EZH2, enhancer of zeste
homologue 2; H3, histone H3; HAT, histone acetyltransferase; HDAC, histone deacet- FACTOR BINDING
ylase; HIF, hypoxia-inducible transcription factor; 5hmC, 5-hydroxymethylcytosine; Chromatin has a major impact on gene expression, mediated through
HMT, histone methyltransferase; HSC, hematopoietic stem cell; IDH, isocitrate interplay with transcription factors. Sequence-specific DNA-binding
dehydrogenase; Ifng promoter, interferon-γ promoter; ISWI, imitation SWI remod- transcription factors are the most important factors in defining whether
eler; MBD, methyl-domain binding; 5mC, 5-methylcytosine; MLL, mixed lineage and when a gene is transcribed, and also define the locations and char-
leukemia; MTA, metastasis-associated; NuRD, nucleosome remodeling and deacet- acter of chromatin regions, as they target chromatin remodeling and
ylation factor; NURF, nucleosome remodeling factor; 2OG, 2-oxoglutarate; PRC2, modifying proteins. However, the initial chromatin landscape can con-
polycomb repressive complex 2; R-2HG, (R)-2-hydroxyglutarate; RAR, retinoic trol whether transcription factors have access to the DNA at a particu-
acid receptor; RNAP II, RNA polymerase II; SDH, succinate dehydrogenase; SRF, lar gene/region. Access to DNA is deterred by nucleosomes, the main
serum response factor; SWI/SNF, switch and sucrose nonfermenting remodeler; repeating unit of chromatin structure, which can block the binding sites
TDG, thymine DNA glycosylase; UHRF1, ubiquitin-like with PHD and ring finger of transcription factors to chromatin. Likewise, DNAme can also block
3
domains; UTX, X-chromosome encoded ubiquitously transcribed tetratricopeptide the binding of transcription factors, many of which will not bind DNA
repeat. if the cytosine in their binding site is methylated (DNAme is discussed
more extensively in the section “DNA Methylation and Demethylation”).

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