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Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE212950 | GEO | 2023/01/23

REPOSITORIES: GEO

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Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation [ATAC-SEq]

Project description:Enhancers are essential in defining cell fates through the control of cell type specific gene expression. Enhancer activation is a multi-step process involving chromatin remodelers and histone modifiers. One of these steps is monomethylation of H3K4 (H3K4me1) by MLL3 (KMT2C) and MLL4 (KMT2D). MLL3/4 are thought to be critical for enhancer activation and cognate gene expression including through the recruitment of acetyltransferases for H3K27. Here we test this model by evaluating the impact of MLL3/4 loss on chromatin and transcription during early embryonic stem cell differentiation. We find that MLL3/4 activity is required at most if not all sites that gain or lose H3K4me1, but is largely dispensable at sites that remain stably methylated during this transition. This requirement extends to H3K27 acetylation (H3K27ac) at most transitional sites. Unexpectedly, many sites gain H3K27ac independent of MLL3/4 or H3K4me1 including enhancers regulating key factors in early differentiation. Furthermore, despite the failure to gain active histone marks at thousands of enhancers, transcriptional activation of nearby genes is largely unaffected, thus uncoupling the regulation of chromatin state from transcriptional changes during this transition. These data challenge current models of enhancer activation and imply distinct mechanisms between stable and dynamically changing enhancers. Moreover, the data suggest limited roles for many enhancers in transcriptional regulation in early ESC differentiation. Collectively, our study highlights gaps in knowledge about the steps and epistatic relationships of enzymes necessary for enhancer activation and cognate gene transcription.

2023-01-23 | GSE212946 | GEO

Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation [CUT&RUN]

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Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation [RNA-Seq]

Project description:Enhancers are essential in defining cell fates through the control of cell type specific gene expression. Enhancer activation is a multi-step process involving chromatin remodelers and modifiers. One of these steps is monomethylation of histone H3 lysine 4 (H3K4m1) by MLL3 (KMT2C) and MLL4 (KMT2D) is thought to be critical for enhancer activation and cognate gene expression including through the recruitment of acetyltransferases targeting H3K27. Here we test this model by evaluating the impact of MLL3/4 loss on chromatin states and gene expression during early embryonic stem cell (ESC) differentiation. We find that MLL3/4 activity is required at most if not all sites that normally gain or lose H3K4m1, but infrequently at sites that remain unchanged during this transition. This requirement extends to H3K27 acetylation (H3K27a) at most transitional sites. Unexpectedly, many sites gain H3K27a independent of MLL3/4 or H3K4m1 including enhancers regulating key factors in early differentiation. Furthermore, despite the failure to gain active histone marks at thousands of enhancers, transcriptional activation of nearby genes is largely unaffected, thus uncoupling enhancer regulation from transcription during this transition. These data challenge current models of enhancer activation and imply distinct mechanisms between stable and dynamically changing enhancers. Moreover, the data suggest limited roles for enhancers in transcriptional regulation in early ESC differentiation. Collectively, our study highlights gaps in knowledge about the steps and epistatic relationships of enzymes necessary for enhancer activation and cognate gene transcription.

2023-01-23 | GSE212948 | GEO

Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation [CUT&TAG]

2023-01-23 | GSE212947 | GEO