Comprehensive benchmarking reveals H2BK20 acetylation as a distinctive signature of cell-state-specific enhancers and promoters

Abstract

Although over 35 different histone acetylation marks have been described, the overwhelming majority of regulatory genomics studies focus exclusively on H3K27ac and H3K9ac. In order to identify novel epigenomic traits of regulatory elements, we constructed a benchmark set of validated enhancers by performing 140 enhancer assays in human T cells. We tested 40 chromatin signatures on this unbiased enhancer set and identified H2BK20ac, a little-studied histone modification, as the most predictive mark of active enhancers. Notably, we detected a novel class of functionally distinct enhancers enriched in H2BK20ac but lacking H3K27ac, which was present in all examined cell lines and also in embryonic forebrain tissue. H2BK20ac was also unique in highlighting cell-type-specific promoters. In contrast, other acetylation marks were present in all active promoters, regardless of cell-type specificity. In stimulated microglial cells, H2BK20ac was more correlated with cell-state-specific expression changes than H3K27ac, with TGF-beta signaling decoupling the two acetylation marks at a subset of regulatory elements. In summary, our study reveals a previously unknown connection between histone acetylation and cell-type-specific gene regulation and indicates that H2BK20ac profiling can be used to uncover new dimensions of gene regulation.

High Resolution Epigenomic Atlas of Early Human Craniofacial Development

“…Defining enriched regions for a single histone modification such as H3K27ac has been utilized to identify active regulatory sequences from a variety of tissues, biological contexts, and different species 36-40 . However, in the absence of H3K27ac, other marks can identify active regulatory sequences, and low levels of H3K27ac may be present at enhancers that are either about to become active or are no longer active 41-43 . More advanced methods, such as using machine learning techniques and integrating multiple chromatin signals from a single tissue, allow segmentation of the genome into a more complex array of biological states 44,45 .…”

Reinstating plasticity and memory in a tauopathy mouse model with an acetyltransferase activator

“…H2BK5ac has already been reported as an important modification associated with active gene transcription in other tissues/cell types (Karlić et al , ). Moreover, H2BK20ac was recently suggested to contribute to cell type–specific gene regulation and biological functions through distal and proximal cis‐regulatory elements (Kumar et al , ). Thus, the decrease in H2Bac in THY‐Tau22 hippocampus may have deleterious functional consequences.…”

High Resolution Epigenomic Atlas of Human Embryonic Craniofacial Development

“…Defining enriched regions for a single histone modification such as H3K27ac has been utilized to identify active regulatory sequences from a variety of tissues, biological contexts, and different species (Cotney et al, 2013;Dickel et al, 2016;Nord et al, 2013;Reilly et al, 2015;Villar et al, 2015). However, in the absence of H3K27ac, other marks can identify active regulatory sequences, and low levels of H3K27ac may be present at enhancers that are either about to become active or are no longer active (Bonn et al, 2012;Cotney et al, 2012;Kumar et al, 2016). More advanced methods, such as using machine-learning techniques and integrating multiple chromatin signals from a single tissue, allow segmentation of the genome into a more complex array of biological states (Ernst and Kellis, 2012;Hoffman et al, 2012).…”