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Determinants and role of chromatin organization in acute leukemia - PubMed

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Determinants and role of chromatin organization in acute leukemia

Celestia Fang et al. Leukemia. 2020 Oct.

Abstract

DNA is compacted into higher order structures that have major implications in gene regulation. These structures allow for long-range interactions of DNA elements, such as the association of promoters with their cognate enhancers. In recent years, mutations in genes that control these structures, including the cohesin-complex and the insulator-binding protein CTCF, have been found in a spectrum of hematologic disorders, and especially in acute leukemias. Cohesin and CTCF are critical for mediating looping and establishing boundaries within chromatin. Cells that harbor mutations in these genes display aberrant chromatin architecture and resulting differences in gene expression that contribute to leukemia initiation and progression. Here, we provide detailed discussion of the nature of 3D interactions and the way that they are disrupted in acute leukemia. Continued research in this area will provide new insights into the mechanisms of leukemogenesis and may shed light on novel treatment strategies.

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Conflict of interest statement

Conflicts of Interest

The authors declare no conflicts of interests.

Figures

Figure 1.
Figure 1.. Working model for the role of CTCF and cohesion in chromatin looping.

a Schematic of a typical promoter:enhancer interaction. These intra-TAD interactions occur when the intervening chromatin segments (black line) are “looped out” to allow the enhancer (green) and promoter (light blue) to directly interact within the nucleus, thereby facilitating gene expression (Dark Blue). Transcription factors (TFs, purple) bind both promoters and enhancers, ultimately resulting in RNA Pol II (Pol II, yellow) producing an mRNA. Active promoters and enhancer can be identified through shared (H3K27Ac) and distinct (H3K4me3-promoters, H3K4me1-enhancers) marks. These interactions are facilitated by CTCF (orange) and/or cohesin (gray). b Schematic of the cohesin complex. Three invariant core subunits (SMC3, SMC1A, and RAD21) and a variable subunit (typically STAG1 or STAG2) form a ring which effectively “handcuffs” the chromatin loop.

Figure 2.
Figure 2.. Models of looping alteration schemes observed in leukemias.

a A pair of CTCF sites can anchor a loop required for active gene expression (left). Deletion of one CTCF site prevents loop formation, thus abrogating gene expression (right). b Silenced genes (left) can require binding of multiple transcription factors to cis-regulatory elements shown in blue. Transcription factor binding induces looping and active gene expression (right).

Figure 3.
Figure 3.. The MYC locus as a model of chromatin looping and associated mechanisms in acute leukemia.

a In normal T cells, the MYC gene is expressed at low levels and is separated from its enhancers by a TAD boundary (demarcated by CTCF binding). b Binding of oncogenic transcription factors such as NOTCH1 and GATA3 as well as recruitment of chromatin remodelers and histone acetylation in the enhancer areas lead to enhancer activation and extensive three-dimensional contacts between the enhancer and MYC in T-cell leukemia upon loss of CTCF from the TAD boundary.

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