Conserved epigenetic regulatory logic infers genes governing cell identity

Abstract

Understanding genetic control of cell diversification is essential for establishing mechanisms controlling biological complexity. This study demonstrates that the a priori deposition of H3K27me3 associated with gene repression across diverse cell states provides a genome-wide metric that enriches for genes governing fundamental mechanisms underlying biological complexity in differentiation, morphogenesis, and disease. We use this metric in combination with more than 1 million genome-wide data sets from diverse omics platforms to identify cell type specific regulatory mechanisms underlying diverse organ systems from species across the animal kingdom. From this analysis, we identify and genetically validate multiple novel genes controlling heart development in diverse chordates including humans and the tunicate, Ciona robusta. This study demonstrates that the conservation of epigenetic regulatory logic provides an effective strategy for utilizing large, diverse genome-wide data to establish quantitative basic principles of cell states to infer cell-type specific mechanisms that underpin the complexity of biological systems. AUTHOR CONTRIBUTIONS WJS:Developed the computational basis for the study, performed data analysis and wrote the manuscript. ES: Assisted in experimental and computational design for the study, performed data analysis, carried out functional genetic studies in hPSCs and wrote the manuscript. JX: Assisted with computational analysis and developed web interactive interface. MA: Performed computational analysis on HF pathogenesis data GA: Performed computational analysis on HF pathogenesis data SS: Assisted the computational analysis on different single-cell data platforms. BB: Performed computational analysis on melanoma studies. YS: Performed computational analysis on Mouse Organogenesis Cell Atlas data. BV: Performed functional analysis on ciona and validated the findings GP: Assisted with spatiotemporal transcriptomic profiling of mouse gastrulation NJ: Assisted with spatiotemporal transcriptomic profiling of mouse gastrulation YW: Helped with computational analysis of epigenetic data MP: Assisted with analysis and interpretation of melanoma data AS: Carried out experiments involving melanoma analysis YC: Carried out experiments involving melanoma analysis PT: Supervised work on spatiotemporal transcriptomic profiling of mouse gastrulation LC: Performed functional analysis on ciona and validated the findings DS: Supervised work on analysis of HF pathogenesis data QN: Provided assistance to implement TRIAGE on single-cell data sets. MB and NJP: Supervised the project, raised funding, and wrote the manuscript.

Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype

“…We recognize that many of the DE genes are likely indirectly affected downstream targets and that key regulatory factors are commonly expressed at relatively low abundance. To enrich for the genes that have a strong potential to be cell identity genes, we implemented TRIAGE (transcriptional regulatory inference analysis from gene expression) 56 alongside the DE analysis. Of note, Gsx1, Gsx2, and Ascl1 were found among the most downregulated genes in the Elp2H206R developing brain (Fig.…”

“…Incorporating epigenetic repressive tendency to identify candidate genes in the transcriptome data. To narrow down a candidate gene set responsible for Elp2 mutant phenotypes, we incorporated the epigenetic repressive tendency score (RTS) into the conventional differential expression analysis output 56 . We calculated a metric that combined both significance of the DE analysis and regulatory importance of individual genes (i.e., pÀvalue from DE analysis repressive tentency score ).…”

“…To understand relevant biological information associated with top-prioritized genes, we performed GO enrichment analysis using DAVID on top 50 genes ranked by the modified p-value using the RTS 56 . Enrichment of selected GO terms (for biological process, cellular component and molecular function categories) and associated genes from both up-and downregulated top 50 genes were visualized with bipartite graphs.…”

TGF-β modulates cell fate in human ES cell-derived foregut endoderm by inhibiting multiple endogenous signaling pathways

“…Indeed, this study suggests that co-binding of OTX2 with either LHX1 or GSC likely determines activation or repression of OTX2 target genes, respectively, in Xenopus anterior development. SIX3, which in addition to anterior neural plate is expressed in hESCderived ME and in early mouse DE (Shim et al, 2020), may also be involved. It is induced, albeit at low levels, by TGF-β1 in our cells and has been shown to repress BMP and WNT ligand expression in anterior neural plate (Gestri et al, 2005;Lagutin et al, 2003).…”

Epigenomic profiling of stem cells within the pilosebaceous unit identifies PRDM16 as a regulator of sebaceous gland homeostasis

“…We previously showed that, by combining H3K27me3 ChIP-seq and RNA-seq profiling, the main regulators of the different cell types found within a heterogeneous population can be identified by those genes that, although highly expressed, are embedded within broad H3K27me3 domains (Rehimi et al, 2016; Schertel et al, 2015; Shim et al, 2020). Using this simple epigenomic approach to dissect epidermal SC heterogeneity, here we identified several putative regulators of non-bulge SCs.…”