Comprehensive 3D epigenomic maps define limbal stem/progenitor cell function and identity

Mingsen Li,Hong Ouyang,Jing Yuan ,Li Wang,Jieying Tan,Junjun Ding,Shaoshuai Jiang,Zhen Mao,Wang Zhang,Jin Zhu,Bofeng Wang,Xihong Lan,Jianping Ji,Liqiong Zhu,Huaxing Huang,Siqi Wu,Fuxi Li,Jiafeng Liu,Yizhi Liu,Chunqiao Liu,Kang Zhang,Huizhen Guo

doi:10.1038/s41467-022-28966-6

Mingsen Li, Hong Ouyang + Show 20 more

Open Access

https://doi.org/10.1038/s41467-022-28966-6

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Abstract

The insights into how genome topology couples with epigenetic states to govern the function and identity of the corneal epithelium are poorly understood. Here, we generate a high-resolution Hi-C interaction map of human limbal stem/progenitor cells (LSCs) and show that chromatin multi-hierarchical organisation is coupled to gene expression. By integrating Hi-C, epigenome and transcriptome data, we characterize the comprehensive 3D epigenomic landscapes of LSCs. We find that super-silencers mediate gene repression associated with corneal development, differentiation and disease via chromatin looping and/or proximity. Super-enhancer (SE) interaction analysis identified a set of SE interactive hubs that contribute to LSC-specific gene activation. These active and inactive element-anchored loop networks occur within the cohesin-occupied CTCF-CTCF loops. We further reveal a coordinated regulatory network of core transcription factors based on SE-promoter interactions. Our results provide detailed insights into the genome organization principle for epigenetic regulation of gene expression in stratified epithelia.

Highlights

The insights into how genome topology couples with epigenetic states to govern the function and identity of the corneal epithelium are poorly understood
We found that the members of gene families related to cellular keratinization, such as LCE, SPRR, and SERPINB families, were arranged in clusters and collectively contained within the same topologically associating domains (TADs) (Fig. 2e)
The clustered cadherin gene superfamily members associated with cell–cell adhesion were located at a TAD, and multiple members were co-regulated when limbal stem/progenitor cells (LSCs) were differentiated into corneal epithelial cells (CECs; Fig. 2f)

Summary

Introduction

The insights into how genome topology couples with epigenetic states to govern the function and identity of the corneal epithelium are poorly understood. We generate a highresolution Hi-C interaction map of human limbal stem/progenitor cells (LSCs) and show that chromatin multi-hierarchical organisation is coupled to gene expression. By integrating Hi-C, epigenome and transcriptome data, we characterize the comprehensive 3D epigenomic landscapes of LSCs. We find that super-silencers mediate gene repression associated with corneal development, differentiation and disease via chromatin looping and/or proximity. Super-enhancer (SE) interaction analysis identified a set of SE interactive hubs that contribute to LSC-specific gene activation These active and inactive element-anchored loop networks occur within the cohesin-occupied CTCF-CTCF loops. Inactive elements, including repressive and heterochromatic regions, are marked by H3K27me[3] and H3K9me[2], respectively[15,16] These active and inactive regulatory regions bound by chromatin regulators influence gene expression via extensive intra-TAD DNA looping in a cell-type-specific manner[17–19]. Our high-resolution chromatin interactome characterizes the 3D regulatory landscape of stratified epithelial stem cells

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