MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK.
Nat Commun. 2022 Jun 17;13(1):3485. doi: 10.1038/s41467-022-31194-7.
The chromatin remodeller ATRX interacts with the histone chaperone DAXX to deposit the histone variant H3.3 at sites of nucleosome turnover. ATRX is known to bind repetitive, heterochromatic regions of the genome including telomeres, ribosomal DNA and pericentric repeats, many of which are putative G-quadruplex forming sequences (PQS). At these sites ATRX plays an ancillary role in a wide range of nuclear processes facilitating replication, chromatin modification and transcription. Here, using an improved protocol for chromatin immunoprecipitation, we show that ATRX also binds active regulatory elements in euchromatin. Mutations in ATRX lead to perturbation of gene expression associated with a reduction in chromatin accessibility, histone modification, transcription factor binding and deposition of H3.3 at the sequences to which it normally binds. In erythroid cells where downregulation of α-globin expression is a hallmark of ATR-X syndrome, perturbation of chromatin accessibility and gene expression occurs in only a subset of cells. The stochastic nature of this process suggests that ATRX acts as a general facilitator of cell specific transcriptional and epigenetic programmes, both in heterochromatin and euchromatin.
染色质重塑因子 ATRX 与组蛋白伴侣 DAXX 相互作用，将组蛋白变体 H3.3 沉积在核小体周转的部位。已知 ATRX 结合基因组的重复、异染色质区域，包括端粒、核糖体 DNA 和着丝粒重复序列，其中许多是推定的 G-四链体形成序列（PQS）。在这些位点，ATRX 在广泛的核过程中发挥辅助作用，促进复制、染色质修饰和转录。在这里，我们使用改良的染色质免疫沉淀（ChIP）协议，表明 ATRX 还结合常染色质中的活性调节元件。ATRX 中的突变导致与染色质可及性降低、组蛋白修饰、转录因子结合和 H3.3 沉积减少相关的基因表达失调，这些序列通常是其结合的靶标。在红细胞中，α-珠蛋白表达的下调是 ATR-X 综合征的一个标志，染色质可及性和基因表达的失调仅发生在部分细胞中。这个过程的随机性表明，ATRX 作为染色质重塑和转录以及表观遗传程序的通用促进剂，在异染色质和常染色质中都发挥作用。
