Analysis of long-range chromatin contacts, compartments and looping between mouse embryonic stem cells, lens epithelium and lens fibers

IF 4.2 2区 生物学 Q1 GENETICS & HEREDITY
Michael Camerino, William Chang, Ales Cvekl
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引用次数: 0

Abstract

Nuclear organization of interphase chromosomes involves individual chromosome territories, “open” and “closed” chromatin compartments, topologically associated domains (TADs) and chromatin loops. The DNA- and RNA-binding transcription factor CTCF together with the cohesin complex serve as major organizers of chromatin architecture. Cellular differentiation is driven by temporally and spatially coordinated gene expression that requires chromatin changes of individual loci of various complexities. Lens differentiation represents an advantageous system to probe transcriptional mechanisms underlying tissue-specific gene expression including high transcriptional outputs of individual crystallin genes until the mature lens fiber cells degrade their nuclei. Chromatin organization between mouse embryonic stem (ES) cells, newborn (P0.5) lens epithelium and fiber cells were analyzed using Hi-C. Localization of CTCF in both lens chromatins was determined by ChIP-seq and compared with ES cells. Quantitative analyses show major differences between number and size of TADs and chromatin loop size between these three cell types. In depth analyses show similarities between lens samples exemplified by overlaps between compartments A and B. Lens epithelium-specific CTCF peaks are found in mostly methylated genomic regions while lens fiber-specific and shared peaks occur mostly within unmethylated DNA regions. Major differences in TADs and loops are illustrated at the ~ 500 kb Pax6 locus, encoding the critical lens regulatory transcription factor and within a larger ~ 15 Mb WAGR locus, containing Pax6 and other loci linked to human congenital diseases. Lens and ES cell Hi-C data (TADs and loops) together with ATAC-seq, CTCF, H3K27ac, H3K27me3 and ENCODE cis-regulatory sites are shown in detail for the Pax6, Sox1 and Hif1a loci, multiple crystallin genes and other important loci required for lens morphogenesis. The majority of crystallin loci are marked by unexpectedly high CTCF-binding across their transcribed regions. Our study has generated the first data on 3-dimensional (3D) nuclear organization in lens epithelium and lens fibers and directly compared these data with ES cells. These findings generate novel insights into lens-specific transcriptional gene control, open new research avenues to study transcriptional condensates in lens fiber cells, and enable studies of non-coding genetic variants linked to cataract and other lens and ocular abnormalities.
分析小鼠胚胎干细胞、晶状体上皮细胞和晶状体纤维之间的长程染色质接触、分区和环路
间期染色体的核组织涉及单个染色体区域、"开放 "和 "封闭 "染色质区、拓扑相关域(TAD)和染色质环。DNA 和 RNA 结合转录因子 CTCF 与粘合素复合物是染色质结构的主要组织者。细胞分化是由时间和空间上协调的基因表达驱动的,这需要不同复杂程度的单个基因座的染色质变化。晶状体分化是探究组织特异性基因表达的转录机制的有利系统,包括在成熟的晶状体纤维细胞降解其细胞核之前单个晶状体蛋白基因的高转录输出。使用 Hi-C 分析了小鼠胚胎干(ES)细胞、新生(P0.5)晶状体上皮细胞和纤维细胞之间的染色质组织。通过 ChIP-seq 确定了 CTCF 在两种晶状体染色质中的定位,并与 ES 细胞进行了比较。定量分析显示,这三种细胞类型的 TAD 数量和大小以及染色质环大小存在很大差异。透镜上皮细胞特异性 CTCF 峰主要出现在甲基化基因组区域,而透镜纤维特异性峰和共享峰主要出现在未甲基化 DNA 区域。在约 500 kb 的 Pax6 基因座(编码关键的晶状体调控转录因子)和较大的约 15 Mb 的 WAGR 基因座(包含 Pax6 和其他与人类先天性疾病相关的基因座)中,TAD 和环的主要差异显而易见。晶状体和 ES 细胞 Hi-C 数据(TAD 和环路)以及 ATAC-seq、CTCF、H3K27ac、H3K27me3 和 ENCODE 顺式调控位点详细显示了 Pax6、Sox1 和 Hif1a 位点、多个晶状体蛋白基因以及晶状体形态发生所需的其他重要位点。大多数晶状体基因位点的转录区都有出乎意料的高 CTCF 结合率。我们的研究首次获得了晶状体上皮细胞和晶状体纤维的三维(3D)核组织数据,并将这些数据与 ES 细胞进行了直接比较。这些发现为晶状体特异性转录基因控制提供了新的见解,为研究晶状体纤维细胞中的转录凝聚物开辟了新的研究途径,并有助于研究与白内障及其他晶状体和眼部异常有关的非编码基因变异。
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来源期刊
Epigenetics & Chromatin
Epigenetics & Chromatin GENETICS & HEREDITY-
CiteScore
7.00
自引率
0.00%
发文量
35
审稿时长
1 months
期刊介绍: Epigenetics & Chromatin is a peer-reviewed, open access, online journal that publishes research, and reviews, providing novel insights into epigenetic inheritance and chromatin-based interactions. The journal aims to understand how gene and chromosomal elements are regulated and their activities maintained during processes such as cell division, differentiation and environmental alteration.
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