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MuvB 复合物结合并稳定细胞周期依赖性基因转录起始位点下游的核小体。

The MuvB complex binds and stabilizes nucleosomes downstream of the transcription start site of cell-cycle dependent genes.

机构信息

Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA, 95064, USA.

Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, CA, 95064, USA.

出版信息

Nat Commun. 2022 Jan 26;13(1):526. doi: 10.1038/s41467-022-28094-1.

DOI:10.1038/s41467-022-28094-1
PMID:35082292
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8792015/
Abstract

The chromatin architecture in promoters is thought to regulate gene expression, but it remains uncertain how most transcription factors (TFs) impact nucleosome position. The MuvB TF complex regulates cell-cycle dependent gene-expression and is critical for differentiation and proliferation during development and cancer. MuvB can both positively and negatively regulate expression, but the structure of MuvB and its biochemical function are poorly understood. Here we determine the overall architecture of MuvB assembly and the crystal structure of a subcomplex critical for MuvB function in gene repression. We find that the MuvB subunits LIN9 and LIN37 function as scaffolding proteins that arrange the other subunits LIN52, LIN54 and RBAP48 for TF, DNA, and histone binding, respectively. Biochemical and structural data demonstrate that MuvB binds nucleosomes through an interface that is distinct from LIN54-DNA consensus site recognition and that MuvB increases nucleosome occupancy in a reconstituted promoter. We find in arrested cells that MuvB primarily associates with a tightly positioned +1 nucleosome near the transcription start site (TSS) of MuvB-regulated genes. These results support a model that MuvB binds and stabilizes nucleosomes just downstream of the TSS on its target promoters to repress gene expression.

摘要

启动子中的染色质结构被认为可以调节基因表达，但大多数转录因子（TFs）如何影响核小体位置仍不确定。MuvB TF 复合物调节细胞周期依赖性基因表达，对于发育和癌症过程中的分化和增殖至关重要。MuvB 可以正向和负向调节表达，但 MuvB 的结构及其生化功能知之甚少。在这里，我们确定了 MuvB 组装的总体结构以及对于 MuvB 在基因抑制功能至关重要的亚基复合物的晶体结构。我们发现，MuvB 的亚基 LIN9 和 LIN37 作为支架蛋白起作用，分别将其他亚基 LIN52、LIN54 和 RBAP48 排列用于 TF、DNA 和组蛋白结合。生化和结构数据表明，MuvB 通过与 LIN54-DNA 共识位点识别不同的界面结合核小体，并且 MuvB 在重组启动子中增加核小体占有率。我们在停滞的细胞中发现，MuvB 主要与 MuvB 调节基因的转录起始位点（TSS）附近紧密定位的+1 核小体相关联。这些结果支持了这样一种模型，即 MuvB 结合并稳定 TSS 下游靶启动子上的核小体，以抑制基因表达。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/cda7482517e1/41467_2022_28094_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/5603662c5125/41467_2022_28094_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/1461b3ab8beb/41467_2022_28094_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/dbb671ac6888/41467_2022_28094_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/5f01321a76c9/41467_2022_28094_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/e5456050f174/41467_2022_28094_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/518baf706101/41467_2022_28094_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/cda7482517e1/41467_2022_28094_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/5603662c5125/41467_2022_28094_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/1461b3ab8beb/41467_2022_28094_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/dbb671ac6888/41467_2022_28094_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/5f01321a76c9/41467_2022_28094_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/e5456050f174/41467_2022_28094_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/518baf706101/41467_2022_28094_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9adb/8792015/cda7482517e1/41467_2022_28094_Fig7_HTML.jpg

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