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QSER1 保护 DNA 甲基化谷免于从头甲基化。

QSER1 protects DNA methylation valleys from de novo methylation.

机构信息

Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.

Developmental Biology Program, Sloan Kettering Institute, 1275 York Avenue, New York, NY 10065, USA.

出版信息

Science. 2021 Apr 9;372(6538). doi: 10.1126/science.abd0875.

DOI:10.1126/science.abd0875
PMID:33833093
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8185639/
Abstract

DNA methylation is essential to mammalian development, and dysregulation can cause serious pathological conditions. Key enzymes responsible for deposition and removal of DNA methylation are known, but how they cooperate to regulate the methylation landscape remains a central question. Using a knockin DNA methylation reporter, we performed a genome-wide CRISPR-Cas9 screen in human embryonic stem cells to discover DNA methylation regulators. The top screen hit was an uncharacterized gene, , which proved to be a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those residing in DNA methylation valleys (or canyons). We further demonstrate genetic and biochemical interactions of QSER1 and TET1, supporting their cooperation to safeguard transcriptional and developmental programs from DNMT3-mediated de novo methylation.

摘要

DNA 甲基化对于哺乳动物的发育至关重要，其调控失常可导致严重的病理状况。人们已经了解了负责 DNA 甲基化沉积和去除的关键酶，但它们如何合作来调控甲基化景观仍是一个核心问题。本研究使用一种基因敲入的 DNA 甲基化报告基因，在人类胚胎干细胞中进行了全基因组 CRISPR-Cas9 筛选，以发现 DNA 甲基化调控因子。该筛选的首要命中靶标是一个尚未被鉴定的基因 ，它被证明是二价启动子和发育基因的活性增强子（即处于 poised 状态的增强子）的关键守护者，尤其是那些位于 DNA 甲基化谷（或峡谷）中的基因。我们进一步证明了 QSER1 和 TET1 之间的遗传和生化相互作用，支持它们合作以防止转录和发育程序被 DNMT3 介导的从头甲基化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/ec3152ca5218/nihms-1701630-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/d7634f72487e/nihms-1701630-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/0c24b111570a/nihms-1701630-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/93b2cace0f67/nihms-1701630-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/7878a03b657e/nihms-1701630-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/040774e304b2/nihms-1701630-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/ec3152ca5218/nihms-1701630-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/d7634f72487e/nihms-1701630-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/0c24b111570a/nihms-1701630-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/93b2cace0f67/nihms-1701630-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/7878a03b657e/nihms-1701630-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/040774e304b2/nihms-1701630-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e1bc/8185639/ec3152ca5218/nihms-1701630-f0007.jpg

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