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首页> 外文期刊>Epigenetics & Chromatin >Interplay between FACT subunit SPT16 and TRIM33 can remodel chromatin at macrophage distal regulatory elements
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Interplay between FACT subunit SPT16 and TRIM33 can remodel chromatin at macrophage distal regulatory elements

机译：FACT亚基SPT16和TRIM33之间的相互作用可以重塑巨噬细胞远端调节元件上的染色质

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Cell type-specific use of cis-acting regulatory elements is mediated by the combinatorial activity of transcription factors involved in lineage determination and maintenance of cell identity. In macrophages, specific transcriptional programs are dictated by the transcription factor PU.1 that primes distal regulatory elements for macrophage identities and makes chromatin competent for activity of stimuli-dependent transcription factors. Although the advances in genome-wide approaches have elucidated the functions of these macrophage-specific distal regulatory elements in transcriptional responses, chromatin structures associated with PU.1 priming and the underlying mechanisms of action of these cis-acting sequences are not characterized. Here, we show that, in macrophages, FACT subunit SPT16 can bind to positioned nucleosomes directly flanking PU.1-bound sites at previously uncharacterized distal regulatory elements located near genes essential for macrophage development and functions. SPT16 can interact with the transcriptional co-regulator TRIM33 and binds to half of these sites in a TRIM33-dependent manner. Using the Atp1b3 locus as a model, we show that FACT binds to two positioned nucleosomes surrounding a TRIM33/PU.1-bound site in a region, located 35?kb upstream the Atp1b3 TSS, that interact with the Atp1b3 promoter. At this ??35?kb region, TRIM33 deficiency leads to FACT release, loss of the two positioned nucleosomes, RNA Pol II recruitment and bidirectional transcription. These modifications are associated with higher levels of FACT binding at the Atp1b3 promoter, an increase of RNA Pol II recruitment and an increased expression of Atp1b3 in Trim33?/? macrophages. Thus, sequestering of SPT16/FACT by TRIM33 at PU.1-bound distal regions might represent a new regulatory mechanism for RNA Pol II recruitment and transcription output in macrophages.
机译：顺式作用调节元件的细胞类型特异性使用是由参与谱系确定和维持细胞身份的转录因子的组合活性介导的。在巨噬细胞中，特定的转录程序受转录因子PU.1的控制，转录因子PU.1启动了巨噬细胞身份的远端调控元件，并使染色质能够胜任刺激依赖性转录因子的活性。尽管全基因组方法的进展已经阐明了这些巨噬细胞特异性远端调控元件在转录反应中的功能，但尚未鉴定与PU.1引发相关的染色质结构和这些顺式作用序列的潜在作用机制。在这里，我们显示，在巨噬细胞中，FACT亚基SPT16可以与定位在直接位于PU.1侧翼的核小体结合，位于先前未表征的远侧调控元件附近，该元件位于巨噬细胞发育和功能必不可少的基因附近。 SPT16可以与转录共调节因子TRIM33相互作用，并以TRIM33依赖性方式与这些位点的一半结合。使用Atp1b3基因座作为模型，我们显示FACT与位于TRIM33 / PU.1结合位点的两个定位的核小体结合，该区域位于Atp1b3 TSS上游35kb，与Atp1b3启动子相互作用。在这个35kbb的区域，TRIM33缺失导致FACT释放，两个定位的核小体丢失，RNA Pol II募集和双向转录。这些修饰与Atp1b3启动子上FACT结合水平的提高，RNA Pol II募集的增加以及Atm1b3在Trim33α/β中的表达增加有关。巨噬细胞。因此，由TRIM33在PU.1结合的远端区域隔离SPT16 / FACT可能代表巨噬细胞中RNA Pol II募集和转录输出的新调控机制。

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