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ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF

ABSTRACT: Gene expression is orchestrated by transcription factors (TFs), which bind to DNA in a sequence-specific manner, and by spatial genome structure, which constrains and shapes TF activity. Zinc finger protein 143 (ZNF143/ZFP143) is a TF that has been implicated in both gene activation and 3D genome organisation. We have generated an acute ZNF143/ZFP143 depletion system to study its direct consequences on chromatin looping and gene transcription. The effects of ZNF143/ZFP143 depletion are inconsistent with it being a looping factor, which we further confirmed by systematic analysis of previous studies. However, degradation of ZNF143/ZFP143 led to the down-regulation of hundreds of its targets, which were found to be enriched in nuclear-encoded mitochondrial genes. By studying the consequences of ZNF143/ZFP143 loss in monoculture and in an in vitro embryonic development model, we establish ZNF143/ZFP143 as a conserved transcriptional regulator of cell proliferation and differentiation by modulating mitochondrial functions.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryonic Stem Cell

SUBMITTER: Liesbeth Hoekman

LAB HEAD: Onno Bleijerveld

PROVIDER: PXD049480 | Pride | 2024-03-08

REPOSITORIES: Pride

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			Action	DRS
	20230609_Exploris_Project_689_DIA_proteome_ZFP_24h_01.raw	Raw
	20230609_Exploris_Project_689_DIA_proteome_ZFP_24h_02.raw	Raw
	20230609_Exploris_Project_689_DIA_proteome_ZFP_24h_03.raw	Raw
	20230609_Exploris_Project_689_DIA_proteome_ZFP_24h_04.raw	Raw
	20230609_Exploris_Project_689_DIA_proteome_ZFP_2h_01.raw	Raw

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Project description:The glucocorticoid receptor (GR) regulates gene expression throughout the human genome in a cell-type-specific manner, governing various aspects of homeostasis. The influence of this transcriptional regulator is seen in multiple pathologies, including cancer. Pharmacological activation of the GR is frequently used to alleviate side-effects caused by therapy for patients with various non-lymphoid solid (i.e. non-hematologic) cancers; however, prior studies have shown that this treatment might also have anti-proliferative action on cancer cells. Nonetheless, the molecular underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the molecular mechanisms of glucocorticoid response in non-lymphoid solid cancers models, focusing on lung cancer. Activation of the GR induces reversible cancer cell dormancy in which cells are tolerant to large array of anti-cancer drugs. This state transition is accompanied by induction of growth factor survival signalling (IGF-1R) and acquired vulnerability to inhibitors of this pathway, both in vitro and in vivo. The observed phenotype is dependent on a single GR target gene - CDKN1C, which encodes for a cell cycle inhibitor protein p57. We have discovered an upstream distal enhancer of CDKN1C, which through GR-induced chromatin looping regulates the expression of this key gene, as confirmed in human tumour specimens. Furthermore, we demonstrate that the SWI/SNF complex composition fine-tunes the GR transcriptional activity at the CDKN1C locus, allowing for precise regulation of cell dormancy induction. Collectively, we show that SWI/SNF-facilitated regulation of CDKN1C underlines GR-induced reversible drug-tolerant state in cancer cells. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anti-cancer therapy related side-effects.

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ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF

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