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A non-canonical tricarboxylic acid cycle underlies cellular identity

ABSTRACT: A non-canonical tricarboxylic acid cycle underlies cellular identity

PROVIDER: PRJNA760776 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15720323_1.fastq.gz	Fastqsanger.gz
	SRR15720323_2.fastq.gz	Fastqsanger.gz
	SRR15720324_1.fastq.gz	Fastqsanger.gz
	SRR15720324_2.fastq.gz	Fastqsanger.gz
	SRR15720325_1.fastq.gz	Fastqsanger.gz

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A non-canonical tricarboxylic acid cycle underlies cellular identity

Project description:The tricarboxylic acid (TCA) cycle is a central hub of cellular metabolism, oxidizing nutrients to generate reducing equivalents for energy production and critical metabolites for biosynthetic reactions. Despite the importance of the products of the TCA cycle for cell viability and proliferation, mammalian cells display diversity in TCA-cycle activity. How this diversity is achieved, and whether it is critical for establishing cell fate, remains poorly understood. Here we identify a non-canonical TCA cycle that is required for changes in cell state. Genetic co-essentiality mapping revealed a cluster of genes that is sufficient to compose a biochemical alternative to the canonical TCA cycle, wherein mitochondrially derived citrate exported to the cytoplasm is metabolized by ATP citrate lyase, ultimately regenerating mitochondrial oxaloacetate to complete this non-canonical TCA cycle. Manipulating the expression of ATP citrate lyase or the canonical TCA-cycle enzyme aconitase 2 in mouse myoblasts and embryonic stem cells revealed that changes in the configuration of the TCA cycle accompany cell fate transitions. During exit from pluripotency, embryonic stem cells switch from canonical to non-canonical TCA-cycle metabolism. Accordingly, blocking the non-canonical TCA cycle prevents cells from exiting pluripotency. These results establish a context-dependent alternative to the traditional TCA cycle and reveal that appropriate TCA-cycle engagement is required for changes in cell state.

2021-12-01 | GSE183434 | GEO

A non-canonical tricarboxylic acid cycle underlies cellular identity.

Project description:The tricarboxylic acid (TCA) cycle is a central hub of cellular metabolism, oxidizing nutrients to generate reducing equivalents for energy production and critical metabolites for biosynthetic reactions. Despite the importance of the products of the TCA cycle for cell viability and proliferation, mammalian cells display diversity in TCA-cycle activity1,2. How this diversity is achieved, and whether it is critical for establishing cell fate, remains poorly understood. Here we identify a non-canonical TCA cycle that is required for changes in cell state. Genetic co-essentiality mapping revealed a cluster of genes that is sufficient to compose a biochemical alternative to the canonical TCA cycle, wherein mitochondrially derived citrate exported to the cytoplasm is metabolized by ATP citrate lyase, ultimately regenerating mitochondrial oxaloacetate to complete this non-canonical TCA cycle. Manipulating the expression of ATP citrate lyase or the canonical TCA-cycle enzyme aconitase 2 in mouse myoblasts and embryonic stem cells revealed that changes in the configuration of the TCA cycle accompany cell fate transitions. During exit from pluripotency, embryonic stem cells switch from canonical to non-canonical TCA-cycle metabolism. Accordingly, blocking the non-canonical TCA cycle prevents cells from exiting pluripotency. These results establish a context-dependent alternative to the traditional TCA cycle and reveal that appropriate TCA-cycle engagement is required for changes in cell state.

| S-EPMC8934290 | biostudies-literature

The lysine demethylase KDM4A controls the cell-cycle expression of replicative canonical histone genes

Project description:Chromatin modulation provides a key checkpoint for controlling cell cycle regulated gene networks. The replicative canonical histone genes are one such gene family under tight regulation during cell division. These genes are most highly expressed during S phase when histones are needed to chromatinize the new DNA template. While this fact has been known for a while, limited knowledge exists about the specific chromatin regulators controlling their temporal expression during cell cycle. Since histones and their associated mutations are emerging as major players in diseases such as cancer, identifying the chromatin factors modulating their expression is critical. The histone lysine tri-demethylase KDM4A is regulated over cell cycle and plays a direct role in DNA replication timing, site-specific rereplication, and DNA amplifications during S phase. Here, we establish an unappreciated role for the catalytically active KDM4A in directly regulating canonical replicative histone gene networks during cell cycle. Of interest, we further demonstrate that KDM4A interacts with proteins controlling histone expression and RNA processing. Together, this study provides a new function for KDM4A in modulating canonical histone gene expression.

2021-10-27 | GSE154684 | GEO

A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in liver

Project description:A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in liver

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Dynamic regulation of chromatin accessibility and transcription factors underlies distinct organ identity and function

Project description:Dynamic regulation of chromatin accessibility and transcription factors underlies distinct organ identity and function

| PRJNA707050 | ENA

Canonical nucleosome organization at promoters forms during genome activation

Project description:The position of nucleosomes influences DNA accessibility to DNA-binding proteins. Genome-wide nucleosome profiles often report the observation of a canonical nucleosome organization at gene promoters where arrays of well-positioned nucleosomes emanate from nucleosome-depleted regions. It is unclear how this canonical promoter nucleosome organization forms and how it is related to transcription activation and the establishment of histone marks during development. Here we report the genome-wide organization of nucleosomes during zebrafish embryogenesis and show that well-positioned nucleosome arrays appear in thousands of promoters during the activation of the zygotic genome. The formation of canonical promoter nucleosome organization cannot be explained by DNA sequence preference, and is independent of transcription and the presence of RNA polymerase II, but strongly correlates with the presence of Histone H3 Lysine 4 trimethylation (H3K4me3). Our study further suggests that promoter nucleosome structure primes genes to future transcription activation. Together, this study reveals that genome activation but not transcription underlies the organization of nucleosome arrays during early embryogenesis. MNase-seq to generate nucleosome organization in two stages of zebrafish development; two biological replicates for each stage. 7 ChIP-seq experiments in three stages.

2013-10-18 | E-GEOD-44269 | biostudies-arrayexpress

Synovial fibroblast positional identity controlled by inductive Notch signaling underlies pathologic damage in inflammatory arthritis

Project description:Synovial fibroblast positional identity controlled by inductive Notch signaling underlies pathologic damage in inflammatory arthritis

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A non-canonical SWI/SNF complex underlies synthetic lethality in cancers driven by BAF complex perturbation

Project description:A non-canonical SWI/SNF complex underlies synthetic lethality in cancers driven by BAF complex perturbation

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The lysine demethylase KDM4A controls the cell-cycle expression of replicative canonical histone genes

Project description:The lysine demethylase KDM4A controls the cell-cycle expression of replicative canonical histone genes

| PRJNA647189 | ENA

Operation of a TCA cycle subnetwork in the mammalian nucleus

Project description:<p>Nucleic acid and histone modifications critically depend on tricarboxylic acid (TCA) cycle for substrates and co-factors. Although a few TCA cycle enzymes have been reported in the nucleus, the corresponding pathways are considered to operate in mitochondria. Here, we show that a part of the TCA cycle is operational also in the nucleus. Using 13C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei of HeLa cells. Proximity labeling mass-spectrometry revealed a spatial vicinity of the involved enzymes with core nuclear proteins. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Nuclear localization of the latter enzyme, which produces succinyl-CoA, changed from pluripotency to differentiated state with accompanying changes in the nuclear protein succinylation. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus warranting a revision of the canonical view on metabolic compartmentalization.</p>

2022-06-15 | MTBLS2235 | MetaboLights

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