Similar Datasets
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
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
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 | GSE212949 | GEO
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 | GSE212947 | GEO
Project description:Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation
| PRJNA878502 | ENA
Project description:Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation [CUT&TAG]
| PRJNA878508 | ENA
Project description:Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation [ATAC-SEq]
| PRJNA878509 | ENA
Project description:Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation [RNA-Seq]
| PRJNA878507 | ENA
Project description:Loss of MLL3/4 decouples enhancer H3K4 monomethylation, H3K27 acetylation, and gene activation [CUT&RUN]
| PRJNA878510 | ENA
Project description:Monomethylation of histone H3 on Lys 4 (H3K4me1) and acetylation of histone H3 on Lys 27 (H3K27ac) are histone modifications that are highly enriched over the body of actively transcribed genes and on enhancers. Although in yeast all H3K4 methylation patterns, including H3K4me1, are implemented by Set1/COMPASS (complex of proteins associated with Set1), there are three classes of COMPASS-like complexes in Drosophila that could carry out H3K4me1 on enhancers: dSet1, Trithorax, and Trithorax-related (Trr). Here, we report that Trr, the Drosophila homolog of the mammalian Mll3/4 COMPASS-like complexes, can function as a major H3K4 monomethyltransferase on enhancers in vivo. Loss of Trr results in a global decrease of H3K4me1 and H3K27ac levels in various tissues. Assays with the cut wing margin enhancer implied a functional role for Trr in enhancer-mediated processes. A genome-wide analysis demonstrated that Trr is required to maintain the H3K4me1 and H3K27ac chromatin signature that resembles the histone modification patterns described for enhancers. Furthermore, studies in the mammalian system suggested a role for the Trr homolog Mll3 in similar processes. Since Trr and mammalian Mll3/4 complexes are distinguished by bearing a unique subunit, the H3K27 demethylase UTX, we propose a model in which the H3K4 monomethyltransferases Trr/Mll3/Mll4 and the H3K27 demethylase UTX cooperate to regulate the transition from inactive/poised to active enhancers.
| S-EPMC3521626 | biostudies-literature