Dataset Information

Operation of a TCA cycle subnetwork in the mammalian nucleus_mass4tox

ABSTRACT: Nucleic acid and histone modifications critically depend on central metabolism for substrates and co-factors. Although a few enzymes related to the formation of these required metabolites have been reported in the nucleus, the corresponding metabolic pathways are considered to function elsewhere in the cell. Here we show that a substantial part of the mitochondrial tricarboxylic acid (TCA) cycle, the biosynthetic hub of epigenetic modification factors, 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, supporting their nuclear location. We further show nuclear localization of aconitase 2 and 2-oxoglutarate dehydrogenase in mouse embryonic stem cells. Together, our results demonstrate operation of an extended metabolic pathway in the nucleus warranting a revision of the canonical view on metabolic compartmentalization and gene expression regulation.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Catarina Franco

LAB HEAD: Kiran Raosaheb Patil

PROVIDER: PXD032238 | Pride | 2022-10-14

REPOSITORIES: Pride

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Operation of a TCA cycle subnetwork in the mammalian nucleus.

Kafkia Eleni E Andres-Pons Amparo A Ganter Kerstin K Seiler Markus M Smith Tom S TS Andrejeva Anna A Jouhten Paula P Pereira Filipa F Franco Catarina C Kuroshchenkova Anna A Leone Sergio S Sawarkar Ritwick R Boston Rebecca R Thaventhiran James J Zaugg Judith B JB Lilley Kathryn S KS Lancrin Christophe C Beck Martin M Patil Kiran Raosaheb KR

Science advances 20220831 35

Nucleic acid and histone modifications critically depend on the tricarboxylic acid (TCA) cycle for substrates and cofactors. 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 <sup>13</sup>C-tracer analysis, we identified activity of glutamine-to-fumarate, citrate-to-succinate, and glutamine-to-aspartate routes in the nuclei o ...[more]

PMID: 36044572

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Project description:modENCODE_submission_3168 Although C. elegans was the first multicellular organism with a completely sequenced genome, how this genome is arranged within the nucleus is not known. By chromatin immunoprecipitation of the nuclear transmembrane protein LEM-2, we determined the regions of the C. elegans genome associated with the nuclear membrane. We found that large regions of several megabases on the left and right arms of each autosome were associated with the nuclear membrane. The center of each autosome was free of such interactions, suggesting these regions are largely looped out from the nuclear membrane. The X chromosome, unlike the autosomes, was associated with the nuclear membrane only at its left end. At a finer scale, these large membrane-associated domains consist of smaller subdomains of LEM-2 associations. These subdomains are characterized by a high density of repetitive sequences, a low density of genes, and high levels of H3K27 trimethylation. The subdomains were punctuated by gaps containing genes with high transcriptional activity. Finally, we found that a chromosome arm translocated to the center of a chromosome retained its association with the nuclear membrane, although there was a decrease of association up to 400 kb from the fusion point. This indicates that local chromatin properties are the main determinant of interaction with the nuclear membrane, but the degree of association can be modulated by position along the chromosome. Our data provide the foundation for a model of the spatial arrangement of C.elegans chromosomes within the nucleus. Supplemental materials are available online at http://www.genome.org . Microarray and high-throughput sequencing data are available online at modENCODE Data Coordinating Center website, http://206.108.121.120/submit/public/list . These dataset are designed to confirm ChIP-chip experiments. The three experiments listed consist of: (1) LEM-2 ChIP-seq (seq-SDQ3891_LEM2_N2_MXemb_1_A_EE8_KI021); (2) control IgG ChIP-seq (seq-AB46540_NIgG_N2_MXemb_2_A_EE1432); and (3)Input-seq (seq-NA_N2_MXemb_3_A_EE1432) For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf

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