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Characterizing age-dependent changes in histone methylation and determine the role of Trr and Trx in histone methylation in adult fly photoreceptors

ABSTRACT: Histone modifications are important for DNA-templated activities, such as transcription. In the first part of this study, we profiled H3K4me2/3, H3K36me3. H3K9me3 and H3K27me3in young (D10) and old (D40) fly photoreceptors using CUT&RUN to characterize global changes in histone methylation during aging. Our data show that both active and repressive marks exhibit consistently decreased levels in photoreceptors cells of old flies compared to young flies. This global decrease in histone methylation suggests an overall reduction in methylation potential in old photoreceptors. In the second part of the same manuscript, we expressed shRNA against mCherry (control), Trr and Trx, two H3K4 methyltransferases, and profile H3K4me1, H3K4me2, and H3K4me3 using CUT&RUN. Our data show that the knockdown of Trr and Trx leads to pronounced decrease in H3K4me3 levels and modest decrease in H3K4me2 and H3K4me1 in adult photoreceptors.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE281054 | GEO | 2026/01/27

REPOSITORIES: GEO

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Project description:FOXA1 is a pioneer factor that is important in hormone dependent cancer cells to stabilise nuclear receptors, such as estrogen receptor (ER) to chromatin. FOXA1 binds to enhancers regions that are enriched in H3K4mono- and dimethylation (H3K4me1, H3K4me2) histone marks and evidence suggests that these marks are requisite events for FOXA1 to associate with enhancers to initate subsequent gene expression events. However, exogenous expression of FOXA1 has been shown to induce H3K4me1 and H3K4me2 signal at enhancer elements and the order of events and the functional importance of these events is not clear. We performed a FOXA1 Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins (RIME) screen in ERα-positive MCF-7 breast cancer cells in order to identify FOXA1 interacting partners and we found histone-lysine N-methyltransferase (MLL3) as the top FOXA1 interacting protein. MLL3 is typically thought to induce H3K4me3 at promoter regions, but recent findings suggest it may contribute to H3K4me1 deposition, in line with our observation that MLL3 associates with an enhancer specific protein. We performed MLL3 ChIP-seq in breast cancer cells and unexpectedly found that MLL3 binds mostly at non-promoter regions enhancers, in contrast to the prevailing hypothesis. MLL3 was shown to occupy regions marked by FOXA1 occupancy and as expected, H3K4me1 and H3K4me2. MLL3 binding was dependent on FOXA1, indicating that FOXA1 recruits MLL3 to chromatin. Motif analysis and subsequent genomic mapping revealed a role for Grainy head like protein-2 (GRHL2) which was shown to co-occupy regions of the chromatin with MLL3. Regions occupied by all three factors, namely FOXA1, MLL3 and GRHL2, were most enriched in H3K4me1. MLL3 silencing decreased H3K4me1 at enhancer elements, but had no appreciable impact on H3K4me3 at enhancer elements. We identify a complex relationship between FOXA1, MLL3 and H3K4me1 at enhancers in breast cancer and propose a mechanism whereby the pioneer factor FOXA1 can interact with a chromatin modifier MLL3, recruiting it to chromatin to facilitate the deposition of H3K4me1 histone marks, subsequently demarcating active enhancer elements.

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Characterizing age-dependent changes in histone methylation and determine the role of Trr and Trx in histone methylation in adult fly photoreceptors

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