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166 Part IV: Molecular and Cellular Hematology Chapter 12: Epigenetics 167

Thus, the nucleosome and DNAme landscape together define the initial CHROMATIN REMODELING
“open versus closed” chromatin state of a region with which the current
repertoire of transcription factors within that cell type must contend. COMPLEXES IN BLOOD
However, this landscape is dynamic, as signaling systems can modify CELL DIFFERENTIATION
transcription factors and chromatin components, altering their activ-
ity and the landscape both through their binding, and through their Clear roles for remodelers in blood cell differentiation are emerging. For
recruitment of nucleosome remodelers and chromatin modifiers. 3–5 example, SWI/SNF components affect the pool size of fetal hemato-
poietic stem cells (HSCs), and also impact HSC (and progenitor) pro-
6
CHROMATIN REMODELERS CONTROL liferation and survival. SWI/SNF complex is also used for myeloid
GENOME ACCESS differentiation to granulocytes and for multiple steps in thymocyte
development. More specifically, in mice SWI/SNF binds the interferon-γ
ATP-dependent chromatin remodeling complexes (termed hereafter (Ifng) promoter, and is required for its full transcription. Furthermore,
remodelers) conduct central roles in regulating nucleosome occupancy mutations in the adenosine triphosphatase (ATPase) function of SWI/
and positioning (Fig. 12–1). For example, remodelers specialized for SNF are known to reduce β-globin expression and to prevent erythroid
3–5
chromatin assembly (such as imitation SWI remodeler [ISWI]-family differentiation. Notably, B-cell lymphoma (BCL) factors BCL7A and
7
and chromodomain remodeler [CHD]-family remodelers) utilize ATP BCL11B, which are considered members of SWI/SNF complex in many
hydrolysis to facilitate tight-packed nucleosomes that lead to the occlu- cell types, are common in hematologic malignancies; for example, muta-
sion of sites for site-specific DNA binding proteins, such as transcrip- tions in BCL7A are found in approximately 20 percent of non-Hodgkin
tion factors. Access to chromatin at enhancers, promoters and other lymphoma and multiple myeloma cases, and mutations in BCL11B
loci can be enabled by remodelers such as the switch and sucrose non- are found in 6 to 12 percent of T-cell acute lymphocytic leukemias
fermenting remodeler (SWI/SNF) complex, also termed the BRG/ (ALLs). 8
BAF-associated factors (BAF) complex, which can slide or eject the his- Roles for ISWI- and CHD-family remodelers include roles for the
tone octamer, using the energy of ATP hydrolysis (Fig. 12–1). Notably, well-characterized CHD-family remodeler nucleosome remodeling and
SWI/SNF can interact with (and facilitate the binding of) DNA-bind- deacetylation factor (NuRD), which interacts with histone deacetylase
ing activators or repressors and can, therefore, help facilitate either (HDAC) enzymes to silence genes. The metastasis-associated (MTA)
activation or repression. Here, the ability of activators or repressors subunits of NuRD help target NuRD subtypes to particular genes
3–5
to interact with SWI/SNF complexes can be influenced by signaling through their interaction with transcription factors and chromatin
cascades, which impart covalent modifications that enable or disable modifications. For example, in B-lymphocytes, MTA3 interacts with
9
protein interactions. Taken together, ISWI and CHD remodelers often BCL6, a major regulator of B-cell differentiation, targeting NuRD
act to silencing genes via site blockage at enhancers and promoters, repression and preventing terminal differentiation into plasma cells.
10
whereas SWI/SNF remodelers promote site exposure at those locations Remarkably, expressing BCL6 in plasma cells while MTA3 is func-
(Fig. 12–1), which is important for gene activation. tional results in a reversion of the cell fate and reprogramming into

SWI/SNF/BAF Figure 12–1. Roles for ATP-dependent chro-
ISWI and CHD Remodelers Remodelers Enable matin remodelers in chromatin assembly or
Conduct Chromatin Assembly Chromatin Acccess chromatin access. Imitation SWI remodelers
D (ISWI)- and chromodomain remodelers (CHD)-
DNA B Site Occlusion family remodelers are involved in chromatin
Deposition of P assembly genome-wide, and also interact with site-
histones following specific repressors to organize nucleosome
DNA replication spacing at genes, which can occlude sites for
DNA-binding proteins. Switch and sucrose nonfer-
menting remodelers (SWI/SNF)-family remodelers
D SWI/SNF Site conduct both nucleosome repositioning/sliding
Random Deposition B Exposure as well as ejection to expose DNA to DNA-binding
P ATP ADP proteins.
Maturation D
ISWI, CHD Assembly B
and Spacing P Repositioning
ATP ADP
OR
D
B
Regular Spacing P Ejection

D
B D
P B DNA-Binding Protein
P
Site blocked
Site Occlusion
DBP binding prevented Site exposed
A B

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