Enhancers with tissue-specific activity are enriched in intronic regions

Borsari, Beatrice; Villegas-Mirón, Pablo; Pérez-Lluch, Sílvia; Turpin, Isabel; Laayouni, Hafid; Segarra-Casas, Alba; Bertranpetit, Jaume; Guigó, Roderic; Acosta, Sandra

doi:10.1101/gr.270371.120

Cited by 33 publications

(23 citation statements)

References 50 publications

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“…This resulted in the identification of 8,855 high‐confidence, putative enhancers, which were present in all three age groups. The majority of these enhancers are located in intronic regions (Fig EV5A ), consistent with a recent report highlighting the predominantly intronic location of tissue‐specific enhancers (Borsari et al , 2021 ). Having identified these liver‐specific enhancers, we then assessed enhancer activity using chromatin accessibility as a proxy.…”

Section: Resultssupporting

confidence: 91%

Aging is associated with increased chromatin accessibility and reduced polymerase pausing in liver

Bozukova

Nikopoulou

Kleinenkuhnen

et al. 2022

Molecular Systems Biology

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Regulation of gene expression is linked to the organization of the genome. With age, chromatin alterations occur on all levels of genome organization, accompanied by changes in the gene expression profile. However, little is known about the changes in the level of transcriptional regulation. Here, we used a multi‐omics approach and integrated ATAC‐, RNA‐ and NET‐seq to identify age‐related changes in the chromatin landscape of murine liver and to investigate how these are linked to transcriptional regulation. We provide the first systematic inventory of the connection between aging, chromatin accessibility, and transcriptional regulation in a whole tissue. Aging in murine liver is characterized by an increase in chromatin accessibility at promoter regions, but not in an increase in transcriptional output. Instead, aging is accompanied by a decrease in promoter‐proximal pausing of RNA polymerase II (Pol II), while initiation of transcription is not decreased as assessed by RNA polymerase mapping using CUT&RUN. Based on the data reported, we propose that these age‐related changes in transcriptional regulation are due to a reduced stability of the pausing complex.

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Section: Resultssupporting

confidence: 91%

Aging is associated with increased chromatin accessibility and reduced polymerase pausing in liver

Bozukova

Nikopoulou

Kleinenkuhnen

et al. 2022

Molecular Systems Biology

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show abstract

“…This resulted in the identification of 8,855 high-confidence, putative enhancers, that were present in all three age groups. The majority of these enhancers are located in intronic regions (Supplementary Figure 8A), consistent with a recent report highlighting the predominantly intronic location of tissue-specific enhancers (Borsari et al , 2021). Having identified these liver-specific enhancers, we then assessed enhancer activity using chromatin accessibility as a proxy.…”

Section: Resultssupporting

confidence: 91%

Reduced polymerase pausing compensates for increased chromatin accessibility in the aging liver

Bozukova

Grbavac

Nikopoulou

et al. 2022

Preprint

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Regulation of gene expression is tightly linked to the organization of the mammalian genome. With age, chromatin alterations occur on all levels of genome organization, accompanied by changes in the gene expression profile. However, little is known about the changes on the level of transcriptional regulation with age. Here, we used a multi-omic approach and integrated ATAC-, RNA- and NET-seq to identify age-related changes in the chromatin landscape of murine liver and to investigate how these are linked to transcriptional regulation. We provide the first systematic inventory of the connection between aging, chromatin accessibility and transcriptional regulation in a whole tissue. We observe that aging in murine liver is accompanied by an increase in chromatin accessibility at promoter regions of protein-coding genes. Yet, although promoter accessibility is a requirement for transcription, the increased accessibility does not result in enhanced transcriptional output. Instead, aging is accompanied by a decrease of promoter-proximal pausing of RNA polymerase II (Pol II). We propose that these changes in transcriptional regulation are due to a reduced stability of the pausing complex and may represent a mechanism to compensate for the age-related increase in chromatin accessibility in order to prevent aberrant transcription

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“…The fraction of H3K18la peaks in intronic regions was highest in the differentiated cell types and lowest in mESC. Interestingly, enhancers with tissue-specific activity were recently reported to be enriched in intronic regions [ 32 ]. Moreover, our genome-wide correlation analyses uncovered that H3K18la resembles H3K27ac (typical marker for active promoters and active enhancers) more than H3K4me3 (typical marker for active promoters but not enhancers).…”

Section: Resultsmentioning

confidence: 99%

H3K18 lactylation marks tissue-specific active enhancers

et al. 2022

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Background Histone lactylation has been recently described as a novel histone post-translational modification linking cellular metabolism to epigenetic regulation. Results Given the expected relevance of this modification and current limited knowledge of its function, we generate genome-wide datasets of H3K18la distribution in various in vitro and in vivo samples, including mouse embryonic stem cells, macrophages, adipocytes, and mouse and human skeletal muscle. We compare them to profiles of well-established histone modifications and gene expression patterns. Supervised and unsupervised bioinformatics analysis shows that global H3K18la distribution resembles H3K27ac, although we also find notable differences. H3K18la marks active CpG island-containing promoters of highly expressed genes across most tissues assessed, including many housekeeping genes, and positively correlates with H3K27ac and H3K4me3 as well as with gene expression. In addition, H3K18la is enriched at active enhancers that lie in proximity to genes that are functionally important for the respective tissue. Conclusions Overall, our data suggests that H3K18la is not only a marker for active promoters, but also a mark of tissue specific active enhancers.

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Enhancers with tissue-specific activity are enriched in intronic regions

Cited by 33 publications

References 50 publications

Aging is associated with increased chromatin accessibility and reduced polymerase pausing in liver

Aging is associated with increased chromatin accessibility and reduced polymerase pausing in liver

Reduced polymerase pausing compensates for increased chromatin accessibility in the aging liver

H3K18 lactylation marks tissue-specific active enhancers

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