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Synthetic transcription factor overrides persistent repressive chromatin marks [RNA-seq]

ABSTRACT: The prevailing paradigms of epigenetic control posit that signature patterns of post-translational marks on histones guide specific transcriptional outcomes. Methylation of lysine-9 residue of histone H3 (H3K9me3) is implicated in transcriptional silencing through chromatin condensation by its reader HP-1 proteins. Erosion, erasure and subsequent replacement of H3K9me3 by active acetyl-lysine marks accompanies transcriptional up-regulation. Here, we report that a synthetic transcription elongation factor (SynTEF1), selectively targets the disease-causing GAA repeat expansion in frataxin and stimulates gene expression without erasure of the signature repressive marks or removal of HP1 proteins. Added epigenetic perturbation with a pharmacological agent leads to supra-synergistic frataxin expression that is unexpectedly accompanied by a dramatic rise in H3K9me3 levels. Active placement of the signature repressive mark is readily overridden by SynTEF1, demonstrating the fluidity and context-dependence of these marks in regulating gene expression. While forcing a reconsideration of how signature epigenetic marks are interpreted, our results provide key insights for therapeutic intervention in rationally reconfiguring disease-associated epigenetic states.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196618 | GEO | 2026/07/02

REPOSITORIES: GEO

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Project description:The expansion of repressive epigenetic marks has been implicated in heterochromatin formation during embryonic development, but the general applicability of this mechanism is unclear. Here we show that nuclear rearrangement of repressive histone marks H3K9me3 and H3K27me3 into non-overlapping structural layers characterizes senescence-associated heterochromatic foci (SAHF) formation in human fibroblasts. However, the global landscape of these repressive marks remains unchanged upon SAHF formation, suggesting that in somatic cells heterochromatin can be formed through the spatial repositioning of pre-existing repressively marked histones. This model is reinforced by the correlation of pre-senescent replication timing with both the subsequent layered structure of SAHFs and the global landscape of the repressive marks, allowing us to integrate microscopic and genomic information. Furthermore, modulation of SAHF structure does not affect the occupancy of these repressive marks nor vice versa. These experiments reveal that high-order heterochromatin formation and epigenetic remodeling of the genome can be discrete events. ChIP-seq for different histone marks in both growing and Ras-induced senescent fibroblasts, in the presence or absence of certain sh-RNAs K9me3Grow2.bed (growing) Chip Seq Analysis of H3K9me3 in ER:Ras expressing IMR90 human diploid fibroblasts d6 4OHT K9me3Sen2.bed (senescent) Chip Seq Analysis of H3K9me3 in ER:Ras expressing IMR90 human diploid fibroblasts with no treatment K9me2Grow3.bed (growing) Chip Seq Analysis of H3K9me2 in ER:Ras expressing IMR90 human diploid fibroblasts with no treatment K9me2Sen3.bed (senescent) Chip Seq Analysis of H3K9me2 in ER:Ras expressing IMR90 human diploid fibroblasts d6 4OHT K27me3Sen3.bed (senescent) Chip Seq Analysis of H3K27me3 in ER:Ras expressing IMR90 human diploid fibroblasts d6 4OHT K27me3Grow2.bed (growing) Chip Seq Analysis of H3K27me3 in ER:Ras expressing IMR90 human diploid fibroblasts with no treatment K36me3Grow2.bed (growing) Chip Seq Analysis of H3K36me3 in ER:Ras expressing IMR90 human diploid fibroblasts with no treatment K36me3Sen2.bed (senescent) Chip Seq Analysis of H3K36me3 in ER:Ras expressing IMR90 human diploid fibroblasts d6 4OHT K4me3Grow2.bed (growing) Chip Seq Analysis of H3K4me3 in ER:Ras expressing IMR90 human diploid fibroblasts with no treatment K4me3Sen3.bed (senescent) Chip Seq Analysis of H3K4me3 in ER:Ras expressing IMR90 human diploid fibroblasts d6 4OHT

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Synthetic transcription factor overrides persistent repressive chromatin marks [RNA-seq]

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