Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

Dave T Gerrard,Dave T Gerrard,Rachel E Jennings,Rachel E Jennings,Rachel E Jennings,Neil A Hanley,Neil A Hanley,Neil A Hanley,Sandra Jiménez-Gancedo,Panos N Firbas,Myles G Garstang,Peyman Zarrineh,Panos N Firbas,Nicoletta Bobola,Nicoletta Bobola,Karen Piper Hanley,Karen Piper Hanley,Karen Piper Hanley,Matthew J Birket,Matthew J Birket,José Luis Gomez-Skarmeta,Sandra Jiménez-Gancedo,Patrick Short,Ian Donaldson,Ian Donaldson,Andrew D Sharrocks,Andrew D Sharrocks,Andrew A Berry,Andrew A Berry,Sarah L Withey,Sarah L Withey,Peyman Zarrineh,Matthew E Hurles,Myles G Garstang

doi:10.1038/s41467-020-17305-2

Abstract

How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development.

Highlights

How the genome activates or silences transcriptional programmes governs organ formation
Thirteen different types of organs and tissues were contributed by 61 human postimplantation embryos, microdissected and subjected to chromatin immunoprecipitation followed by deep sequencing (ChIPseq) for three histone modifications (Fig. 1a): H3K4me[3], enriched at promoters of transcribed genes; H3K27ac, at active enhancers and some promoters; and H3K27me[3] delineating regions of the genome under active repression by Polycomb
Overlaying the data revealed characteristic tissue-specific patterns of promoter and putative enhancer activity, and unannotated human embryonic transcripts. This was noticeable surrounding genes encoding key developmental transcription factors (TFs), such as the example shown for NKX2-5 in the heart (Fig. 1b)

Summary

Introduction

How the genome activates or silences transcriptional programmes governs organ formation. The non-coding genome harbours over 80% of single-nucleotide polymorphisms (SNPs) implicated in genome-wide association studies (GWAS) for developmental disorders, or in GWAS of later onset disease, such as schizophrenia and type 2 diabetes, where contribution is predicted from early development[3] These genetic alterations are presumed to lie in enhancers for developmental genes or in other regulatory elements, such as promoters for non-coding RNAs that may only be active in the relevant tissue at the appropriate stage of organogenesis. Nothing is known about patterns of regulation, including both activation and repression, deployed across tissues, which is an important factor because tissues are often co-affected in developmental disorders To address these gaps in our knowledge, we set out to build maps of genome regulation integrated with transcription during human organogenesis at comprehensiveness currently unattainable from single-cell analysis

Methods

Results

Conclusion