Inborn Error of Cobalamin Metabolism Associated with the Intracellular Accumulation of Transcobalamin-Bound Cobalamin and Mutations in<i>ZNF143</i>, Which Codes for a Transcriptional Activator

Pupavac, Mihaela; Watkins, David; Petrella, Francis; Fahiminiya, Somayyeh; Janer, Alexandre; Cheung, Warren A.; Gingras, Anne‐Claude; Pastinen, Tomi; Muenzer, Joseph; Majewski, Jacek; Shoubridge, Eric A.; Rosenblatt, David S.

doi:10.1002/humu.23037

Cited by 36 publications

(14 citation statements)

References 32 publications

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“…HCFC1 encodes for a transcriptional co-activator that regulates genes important for metabolism and proliferation (12). It is suggested that HCFC1 binds to and regulates the expression of >5000 different genes (18), with various different interacting partners including THAP11 (13) and ZNF143 (49), where mutation of either can cause a cblX like disorder (16,50).…”

Section: Discussionmentioning

confidence: 99%

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain

Castro

Reyes

Reyes-Nava

et al. 2019

Preprint

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Background: Precise regulation of neural precursor cell (NPC) proliferation and differentiation is essential to ensure proper brain development and function. The HCFC1 gene encodes a transcriptional co-factor that regulates cell proliferation, and previous studies suggest that HCFC1 regulates NPC function. However, the molecular mechanism underlying these cellular deficits has not been completely characterized. Methods: Here we created a zebrafish harboring mutations in the hcfc1a gene (the hcfc1aco60/+ allele), one ortholog of HCFC1, and utilized immunohistochemistry and RNA-sequencing technology to understand the function of hcfc1a during neural development.Results: The hcfc1aco60/+ allele results in an increased number of NPCs, neurons, and radial glial cells. These deficits are associated with the abnormal expression of asxl1, a polycomb transcription factor, which we identified as a downstream effector of hcfc1a using high throughput RNA sequencing technology. Inhibition of asxl1 activity and/or expression in larvae harboring the hcfc1aco60/+ allele completely restored the number of NPCs to normal levels. Conclusion: Collectively, our data demonstrate a novel pathway in which hcfc1a regulates NPCs and neurogenesis.

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Section: Discussionmentioning

confidence: 99%

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain

Castro

Reyes

Reyes-Nava

et al. 2019

Preprint

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“…Control of the cell cycle by HCFC1 has been shown to require formation of a complex with the transcription factors THAP domain‐containing protein 11 (THAP11) and zinc finger protein 143 (ZNF143) . Indeed, mutation of both THAP11 and ZNF143 has been shown to result in loss of MMACHC expression and clinical Cbl deficiency, thus demonstrating that this complex is also involved in MMACHC expression. This provides a link between Cbl cofactor synthesis and cell growth and proliferation, which connects the methionine and one‐carbon cycles as well (see below).…”

Section: Allosteric Genetic and Epigenetic Regulationmentioning

confidence: 99%

Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

Froese

Fowler

Baumgartner

2019

J of Inher Metab Disea

304

187

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Vitamin B12 (cobalamin, Cbl) is a nutrient essential to human health. Due to its complex structure and dual cofactor forms, Cbl undergoes a complicated series of absorptive and processing steps before serving as cofactor for the enzymes methylmalonyl‐CoA mutase and methionine synthase. Methylmalonyl‐CoA mutase is required for the catabolism of certain (branched‐chain) amino acids into an anaplerotic substrate in the mitochondrion, and dysfunction of the enzyme itself or in production of its cofactor adenosyl‐Cbl result in an inability to successfully undergo protein catabolism with concomitant mitochondrial energy disruption. Methionine synthase catalyzes the methyl‐Cbl dependent (re)methylation of homocysteine to methionine within the methionine cycle; a reaction required to produce this essential amino acid and generate S‐adenosylmethionine, the most important cellular methyl‐donor. Disruption of methionine synthase has wide‐ranging implications for all methylation‐dependent reactions, including epigenetic modification, but also for the intracellular folate pathway, since methionine synthase uses 5‐methyltetrahydrofolate as a one‐carbon donor. Folate‐bound one‐carbon units are also required for deoxythymidine monophosphate and de novo purine synthesis; therefore, the flow of single carbon units to each of these pathways must be regulated based on cellular needs. This review provides an overview on Cbl metabolism with a brief description of absorption and intracellular metabolic pathways. It also provides a description of folate‐mediated one‐carbon metabolism and its intersection with Cbl at the methionine cycle. Finally, a summary of recent advances in understanding of how both pathways are regulated is presented.

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“…Wei et al (2016) have found that ZNF143 expression can enhance the metastasis of gastric cancer cells, indicating that ZNF143 can be a drug target for the treatment of gastric cancer. The reduction in ZNF143 expression eventually leads to the cobaltamine transport protein not effectively transporting cobalamin (Pupavac et al, 2016). The expression patterns of ZNF143 and ZNF281 in serous borderline ovarian tumors (SBOTs) and low-grade epithelial ovarian carcinomas (EOCs) play a key role in cancer invasion, metastasis formation, and chemotherapy resistance (Sadlecki et al, 2019).…”

Section: Potential Drug Design Targetmentioning

confidence: 99%

ZNF143 in Chromatin Looping and Gene Regulation

Yang

et al. 2020

Front. Genet.

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ZNF143, a human homolog of the transcriptional activator Staf, is a C2H2-type protein consisting of seven zinc finger domains. As a transcription factor (TF), ZNF143 is sequence specifically binding to chromatin and activates the expression of protein-coding and non-coding genes on a genome scale. Although it is ubiquitous expressed, its expression in cancer cells and tissues is usually higher than that in normal cells and tissues. Therefore, abnormal expression of ZNF143 is related to cancer cell survival, proliferation, differentiation, migration, and invasion, suggesting that new small molecules can be designed by targeting ZNF143 as it may be a good potential biomarker and therapeutic target for related cancers. However, the mechanism on how ZNF143 regulates its targeting gene remains unclear. Recently, with the development of chromatin conformation capture (3C) and its derivatives, and high-throughput sequencing technology, new findings have been obtained in the study of ZNF143. Pioneering studies have showed that ZNF143 binds directly to promoters and contributes to chromatin interactions connecting promoters to distal regulatory elements, such as enhancers. Further, it has proved that ZNF143 is involved in CCCTCbinding factor (CTCF) in establishing the conserved chromatin loops by cooperating with cohesin and other partners. These results indicate that ZNF143 is a key loop formation factor. In addition, we report ZNF143 is dynamically bound to chromatin during the cell cycle demonstrated that it is a potential mitotic bookmarking factor. It may be associated with CTCF for mitosis-to-G1 phase transition and chromatin loop re-establishment in early G1 phase. In the future, researchers could further clarify the fine mechanism of ZNF143 in mediating chromatin loops with the help of CUT&RUN (CUT&Tag) and Cut-C technology. Thus, in this review, we summarize the research progress of TF ZNF143 in detail and also predict the potential functions of ZNF143 in cell fate and identity based on our recent discoveries.

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Inborn Error of Cobalamin Metabolism Associated with the Intracellular Accumulation of Transcobalamin-Bound Cobalamin and Mutations inZNF143, Which Codes for a Transcriptional Activator

Cited by 36 publications

References 32 publications

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain

Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

ZNF143 in Chromatin Looping and Gene Regulation

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Inborn Error of Cobalamin Metabolism Associated with the Intracellular Accumulation of Transcobalamin-Bound Cobalamin and Mutations inZNF143, Which Codes for a Transcriptional Activator

Cited by 36 publications

References 32 publications

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain

Hcfc1a regulates neural precursor proliferation and asxl1 expression in the developing brain

Vitamin B12, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

ZNF143 in Chromatin Looping and Gene Regulation

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Resources

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Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation