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Epigenetic and transcriptional regulation of starvation-induced atrophy and autophagy programs by Foxk1 and Sin3A

ABSTRACT: Autophagy is the primary catabolic process triggered in response to starvation. Although autophagic regulation within the cytosolic compartment is well established, it is becoming clear that nuclear events also regulate the induction or repression of autophagy. Nevertheless, a thorough understanding of the mechanisms by which sequence-specific transcription factors modulate expression of genes required for autophagy is lacking. Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy in muscle cells and fibroblasts. Interestingly, Foxk1/2 serve to counter-balance another forkhead transcription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets in muscle. Foxk1/2 specifically recruits Sin3A-HDAC complexes to restrict acetylation of histone H4 and expression of critical autophagy genes. Remarkably, mTOR promotes the transcriptional activity of Foxk1 by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions. Our study highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR to restrict autophagy by repressing essential autophagy genes via Foxk-Sin3-mediated transcriptional control.

ORGANISM(S): Mus musculus

PROVIDER: GSE56932 | GEO | 2014/11/17

SECONDARY ACCESSION(S): PRJNA244979

REPOSITORIES: GEO

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Epigenetic and transcriptional regulation of starvation-induced atrophy and autophagy programs by Foxk1 and Sin3A

Project description:Autophagy is the primary catabolic process triggered in response to starvation. Although autophagic regulation within the cytosolic compartment is well established, it is becoming clear that nuclear events also regulate the induction or repression of autophagy. Nevertheless, a thorough understanding of the mechanisms by which sequence-specific transcription factors modulate expression of genes required for autophagy is lacking. Here, we identify Foxk proteins (Foxk1 and Foxk2) as transcriptional repressors of autophagy in muscle cells and fibroblasts. Interestingly, Foxk1/2 serve to counter-balance another forkhead transcription factor, Foxo3, which induces an overlapping set of autophagic and atrophic targets in muscle. Foxk1/2 specifically recruits Sin3A-HDAC complexes to restrict acetylation of histone H4 and expression of critical autophagy genes. Remarkably, mTOR promotes the transcriptional activity of Foxk1 by facilitating nuclear entry to specifically limit basal levels of autophagy in nutrient-rich conditions. Our study highlights an ancient, conserved mechanism whereby nutritional status is interpreted by mTOR to restrict autophagy by repressing essential autophagy genes via Foxk-Sin3-mediated transcriptional control. Examination of (1) chromatin binding of Foxk1 and Sin3A in non-starved myoblasts and (2) gene expression profiling upon either starvation or siRNA-mediated depletion of Foxk1 relative to a non-starved control.

2014-11-17 | E-GEOD-56932 | biostudies-arrayexpress

FoxK1/2 – New Components in Insulin Regulation of Cellular and Mitochondrial Metabolism

Project description:A major target of insulin signaling is the FoxO family of Forkhead transcription factors, which translocate from the nucleus to the cytoplasm following insulin-stimulated phosphorylation. Here we show that the Forkhead transcription factors FoxK1 and FoxK2 are also downstream targets of insulin action, but that following insulin stimulation, they translocate from the cytoplasm to nucleus, reciprocal to the translocation of FoxO1. FoxK1/FoxK2 translocation to the nucleus is dependent on the Akt-mTOR pathway, while its localization to the cytoplasm in the basal state is dependent on GSK3. Knockdown of FoxK1 and FoxK2 in liver cells results in upregulation of genes related to apoptosis and down-regulation of genes involved in cell cycle and lipid metabolism. This is associated with decreased cell proliferation and altered mitochondrial fatty acid metabolism. Thus, FoxK1/K2 are reciprocally regulated to FoxO1 following insulin stimulation and play a novel role in the control of apoptosis, metabolism and mitochondrial function.

2019-02-25 | GSE110574 | GEO

RNA-seq of human embryonic stem cells H1 ESC cells and the differentiated NPC cells with FOXK1/2 and SIN3A knock down and the control condition.

Project description:In order to investigate the genome-wide binding profile of the forkhead transcription factor FOXK2 in human embryonic stem cells (ESCs) and downstream cell types, we generated the RNA-seq data with FOXK1/2 and SIN3A siRNA in H1 ESC cells and FOXK1/2 siRNA in the differentiated NPC cells.

2021-09-08 | E-MTAB-9639 | biostudies-arrayexpress

Comparative transcriptomic analysis of WT, FOXK1/2 KO, DKO cells and FOXK1 KO cells with reconstitution of several FOXK1 mutants

Project description:The goal of this study was to apply Next Generation Sequencing analyses to identify genes and pathways regulated by the FOXK1 and FOXK2 transcription factor in HeLa cells and to see whether reconstitution of FOXK1 WT and mutants can rescue the altered gene regulation in FOXK1 KO cells. Gene Ontology (GO) analysis did not uncover any dysregulated DNA damage–related pathways upon FOXKs KO. We found that cells reconstituted with any of the three FOXK1 mutants could largely rescue dysregulated gene expression in FOXK1 KO cells, similar to cells reconstituted with WT FOXK1. These suggesting that FOXK1's role in DNA damage response is not by direct transcriptional regulation of DNA damage related pathways and all the three FOXK1 mutants could not affect transcription.

2020-06-26 | GSE151029 | GEO

Gene regulated by mutant ASXL1 KO and FOXK1/FOXK2 KO in K562 cell line

Project description:Gene regulated by mutant ASXL1 KO and FOXK1/FOXK2 KO in K562 cell line

2021-03-01 | GSE146159 | GEO

Comparative transcriptomic analysis of 3T3-L1 adipocytes with modulated level of Foxk1 and Foxk2 transcription factor

Project description:The goal of this study was to apply Next Generation Sequencing analyses to identify genes and pathways regulated by the Foxk1 and Foxk2 transcription factor in 3T3-L1 adipocytes. We found, that series of enzymes involved in metabolism of lipids and carbohydrates, as well as cell migration, proliferation and adhesion are regulated in response to this transcription factor, thereby providing important insight into biological role of Foxk1 and Foxk2 for cells survival and metabolism.

2018-12-01 | GSE114258 | GEO

Depletion of Foxk transcription factors causes genome-wide transcriptional misregulation and developmental arrest in zebrafish embryos

Project description:Foxk proteins are transcriptional regulators implicated in key biological processes such as glycolysis, autophagy and cell cycle regulation, among others. Here we employ targeted morpholino knockdown to deplete Foxk1, Fokx2, and Foxk2-1 proteins in developing zebrafish embryos. We demonstrate that the loss of Foxk transcription factors causes genome-wide transcriptional misregulation, characterised by upregulation of autophagy-related genes and downregulation of cell cycle regulators. The phenotype is embryonic lethal with the majority of embryos not surviving past 24hpf.

2020-12-01 | E-MTAB-9777 | biostudies-arrayexpress

RNA-seq datasets from differentiating iHA-Foxk1 and Foxk1 KO mESCs in mesodermal conditions

Project description:D3, D5 and D10 EBs from iHA-Foxk1 and Foxk1 KO cells were harvested for RNA and submitted for sequencing to understand the transcriptional profile of these cells during differentiation in the presence and absence of FOXK1

2023-05-08 | GSE202562 | GEO

ATAC-seq datasets from differentiating iHA-Foxk1 and Foxk1 KO mESCs in mesodermal conditions

Project description:50k cells from D3, D5 and D10 EBs from iHA-Foxk1 and Foxk1 KO cells were harvested for ATAC-seq and submitted for sequencing to understand the chromatin dynamics of these cells during differentiation in the presence and absence of FOXK1

2023-05-08 | GSE202517 | GEO

Phase separation mediated transcriptional activity of FOXK1 triggers glycolysis and facilitates renal fibrosis

Project description:Tubular epithelial cells (TECs) undergo an energy metabolism shift from fatty acid oxidation (FAO) to glycolysis in renal fibrosis. The critical pathways leading to the halt of FAO in TECs have been well described, whereas the mechanism underlying the burst of glycolysis remains elusive. We herein reported a critical glycolysis regulator emerged in TECs amid the renal fibrosis, the transcriptional factor forkhead box protein K1 (FOXK1), which exhibited fibrogenic and metabolism-rewiring capacity. Genetic modification of FOXK1 in TECs altered the glycolytic metabolism and fibrotic lesion. The surge of a set of glycolysis-related genes following FOXK1 activation contributed to the energic shift. Nuclear-translocated FOXK1 formed condensates through liquid-liquid phase separation (LLPS) to drive the target genes transcription. The core intrinsically disordered regions (IDRs) within FOXK1 were further mapped and validated. Finally, we explored the therapeutic strategy targeting Foxk1 in the CKD mouse model by subcapsular injecting Foxk1-shRNA-carrying AAV9 vector.

2024-02-29 | GSE253528 | GEO

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