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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

O-GlcNAcylation of FOXK1 orchestrates the E2F pathway

Project description:Gene transcription is a highly regulated process, and deregulation of transcription factors activity underlie numerous pathologies including cancer. FOXK1 and FOXK2 (FOXK1/2) transcription factors have recently emerged as important regulators of cell metabolism, autophagy and cell differentiation. While FOXK1/2 possesses many overlapping functions in normal biology, their specific functions as well as deregulation of their transcriptional activity in cancer is less clear and often contradictory. FOXK1, but less FOXK2, is known to have oncogenic properties as higher expression levels of FOXK1 has been observed in several cancers and is correlated with tumor progression, invasion, and metastasis. However, the molecular mechanism by which FOXK1 exert its oncogenic properties in caner remains unknown. Here we show that elevated expression of FOXK1, but not FOXK2, in normal human fibroblasts promotes transcription of E2F target genes associated with increased proliferation and delayed senescence entry. Fibroblasts overexpressing FOXK1 are also more prone to cellular transformation with minimal oncogenic combinations, suggesting important oncogenic proprieties of FOXK1. Mechanistically, we found that FOXK1, but not FOXK2, is specifically modified by O-GlcNAcylation. FOXK1 O-GlcNAcylation is modulated during the cell cycle and its highest levels coincides with the G1/S phase transition. Moreover, FOXK1 O-GlcNAcylation is increased following cell transformation and loss of this modification leads to decreased FOXK1 ability to promote cellular transformation and tumor growth. Cells overexpressing FOXK1 O-GlcNAcylation-defective mutants have lower E2F1 expression, cell proliferation, and tumour growth. Our results define a distinct role of FOXK1 via O-GlcNAcylation in controlling the cell cycle through the orchestration of the E2F pathway.

2024-06-10 | PXD050014 | Pride

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

FoxK1 and FoxK2 cooperate with ORF45 to promote late lytic replication of Kaposi’s sarcoma-associated herpesvirus

Project description:Lytic replication is essential for persistent infection of Kaposi’s sarcoma-associated herpesvirus (KSHV) and the pathogenesis of related diseases, and many cellular pathways are hijacked by KSHV proteins to initiate and control the lytic replication of this virus. However, the machinery involved in KSHV lytic replication from the early to the late phases remains largely undetermined. We previously revealed that KSHV ORF45 plays important roles in late transcription and translation. In the present study, we reveal that the Forkhead box proteins FoxK1 and FoxK2 are ORF45-binding proteins and are essential for KSHV lytic gene expression and virion production and that depletion of FoxK1 or FoxK2 significantly suppresses the expression of many late viral genes. FoxK1 and FoxK2 directly bind to the promoters of several late viral genes, ORF45 augments the promoter binding and transcriptional activity of FoxK1 and FoxK2, and then FoxK1 or FoxK2 cooperates with ORF45 to promote late viral gene expression. Our findings suggest that ORF45 interacts with FoxK1 and FoxK2 and promotes their occupancy on a cluster of late viral promoters and their subsequent transcriptional activity; consequently FoxK1 and FoxK2 promote late gene expression to facilitate KSHV lytic replication.

2024-08-05 | GSE273577 | GEO

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

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