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Fig. 3 | Journal of Hematology & Oncology

Fig. 3

From: ASXL1/2 mutations and myeloid malignancies

Fig. 3

ASXL1/2 and multiprotein complex regulation of gene expression by histone modifications. ASXL1 and ASXL2 each associates with the histone methyl transferase EZH1/2, SUZ12, EED and RbAp46/48 to form a complex (i.e., PRC2) that recognizes H2AK119Ub1, and methylates H3K27 (H3K27me1/2/3) leading to the silencing of target genes. PRC1 complexes contain an E3 ubiquitin ligase that monoubiquitinates H2AK119 (H2AK119Ub1). The CBX protein of canonical PRC1 (cPRC1) binds H3K27me3, which enables H2AK119Ub1 deposition, and additionally interacts with nucleosomes for chromatin compaction and transcriptional repression. The variant PRC1 (vPRC1) recognizes H2AK119Ub1 via RYBP or YAF2 to propagate H2AK119Ub1. PR-DUB complex, comprised of ASXL1 or ASXL2, the deubiquitinase BAP1, and various interacting proteins, deubiquitinates H2AK119Ub1 resulting in the derepression of target genes. Loss of Asxl1 in HSC/HPCs has been shown to cause a global loss of H3K27me3 and the increased expression of leukemogenic genes. ASXL1 truncation mutations result in a hyperactive mutation-ASXL1/BAP1 complex that depletes H2AK119Ub1 resulting in a loss of H3K27me3 and increased expression of leukemogenic genes. ASXL2 loss in HSC/HPCs results in a slight reduction of H3K27me3 levels

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