Lens differentiation is characterized by stage-specific changes in chromatin accessibility correlating with differentiation state-specific gene expression
Lens differentiation is characterized by stage-specific changes in chromatin accessibility correlating with differentiation state-specific gene expression
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DOI：
10.1016/j.ydbio.2019.04.020
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发表时间：
2019-09-01
影响因子：
2.7
通讯作者：
Kantorow, Marc
中科院分区：
文献类型：
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作者：
Disatham, Joshua;Chauss, Daniel;Kantorow, Marc
染色质可及性的改变通过控制转录因子进入关键基因调控序列来调节多个基因的表达。在这里，我们试图建立一个潜在的功能，改变染色质可及性控制关键基因表达事件在透镜细胞分化，通过建立全基因组染色质可及性地图特定的四个不同阶段的透镜细胞分化和相关的特定变化，染色质可及性与全基因组的基因表达的变化。采用ATAC测序产生染色质可及性谱，其与在透镜细胞分化的相同阶段通过高通量RNA测序获得的超过10，000个透镜基因的表达谱相关。透镜基因组的大约90，000个区域在透镜分化的一个或多个阶段表现出染色质可及性的明显变化。超过1000个基因在透镜细胞分化的特定阶段的表达水平变化与潜在启动子（转录起始位点的-7.5kbp/+2.5kbp）和/或其他潜在顺式调控区（基因体的+/-10kb）的染色质可及性变化之间表现出高Pearson相关系数（r > 0.7）。对这些区域的分析鉴定了多种转录因子的共有结合序列，包括转录因子的TEAD、FOX和NFAT家族的成员以及HIF 1a、RBPJ和IRF 1。对改变的染色质可及性和分化状态特异性基因表达变化之间具有高度相关性的基因进行功能定位，鉴定了多个蛋白质家族，其表达可以通过染色质可及性的变化进行调节，包括那些控制透镜结构的蛋白质（BFSP 1，BFSP 2），基因表达（Pax-6，Sox 2），翻译（TDRD 7），细胞间通讯（GJA 1），自噬（FYCO 1），信号转导（SMAD 3、EPHA 2）和透镜透明度（透镜BB 1、透镜BA 4）。这些数据提供了改变的染色质可及性和透镜分化之间的新关系，并且它们鉴定了可以通过改变的染色质可及性来调节的各种各样的透镜基因和功能。这些数据还指出了大量潜在的DNA调控序列和转录因子，其功能分析可能提供新的监管机制，管理透镜分化程序的洞察力。
Changes in chromatin accessibility regulate the expression of multiple genes by controlling transcription factor access to key gene regulatory sequences. Here, we sought to establish a potential function for altered chromatin accessibility in control of key gene expression events during lens cell differentiation by establishing genome-wide chromatin accessibility maps specific for four distinct stages of lens cell differentiation and correlating specific changes in chromatin accessibility with genome-wide changes in gene expression. ATAC sequencing was employed to generate chromatin accessibility profiles that were correlated with the expression profiles of over 10,000 lens genes obtained by high-throughput RNA sequencing at the same stages of lens cell differentiation. Approximately 90,000 regions of the lens genome exhibited distinct changes in chromatin accessibility at one or more stages of lens differentiation. Over 1000 genes exhibited high Pearson correlation coefficients (r > 0.7) between altered expression levels at specific stages of lens cell differentiation and changes in chromatin accessibility in potential promoter (-7.5kbp/+2.5kbp of the transcriptional start site) and/or other potential cis-regulatory regions (+/- 10 kb of the gene body). Analysis of these regions identified consensus binding sequences for multiple transcription factors including members of the TEAD, FOX, and NFAT families of transcription factors as well as HIF1a, RBPJ and IRF1. Functional mapping of genes with high correlations between altered chromatin accessibility and differentiation state-specific gene expression changes identified multiple families of proteins whose expression could be regulated through changes in chromatin accessibility including those governing lens structure (BFSP1,BFSP2), gene expression (Pax-6, Sox 2), translation (TDRD7), cell-cell communication (GJA1), autophagy (FYCO1), signal transduction (SMAD3, EPHA2), and lens transparency (CRYBB1, CRYBA4). These data provide a novel relationship between altered chromatin accessibility and lens differentiation and they identify a wide-variety of lens genes and functions that could be regulated through altered chromatin accessibility. The data also point to a large number of potential DNA regulatory sequences and transcription factors whose functional analysis is likely to provide insight into novel regulatory mechanisms governing the lens differentiation program.