Dataset Information

Histone lactylation drives oncogenesis by facilitating m⁶A reader protein YTHDF2 expression in ocular melanoma.

ABSTRACT:

Background

Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear.

Results

Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mechanistically, histone lactylation contributes to tumorigenesis by facilitating YTHDF2 expression. Moreover, YTHDF2 recognizes the m6A modified PER1 and TP53 mRNAs and promotes their degradation, which accelerates tumorigenesis of ocular melanoma.

Conclusion

We reveal the oncogenic role of histone lactylation, thereby providing novel therapeutic targets for ocular melanoma therapy. We also bridge histone modifications with RNA modifications, which provides novel understanding of epigenetic regulation in tumorigenesis.

SUBMITTER: Yu J

PROVIDER: S-EPMC7962360 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Histone lactylation drives oncogenesis by facilitating m<sup>6</sup>A reader protein YTHDF2 expression in ocular melanoma.

Yu Jie J Chai Peiwei P Xie Minyue M Ge Shengfang S Ruan Jing J Fan Xianqun X Jia Renbing R

Genome biology 20210316 1

<h4>Background</h4>Histone lactylation, a metabolic stress-related histone modification, plays an important role in the regulation of gene expression during M1 macrophage polarization. However, the role of histone lactylation in tumorigenesis remains unclear.<h4>Results</h4>Here, we show histone lactylation is elevated in tumors and is associated with poor prognosis of ocular melanoma. Target correction of aberrant histone lactylation triggers therapeutic efficacy both in vitro and in vivo. Mech ...[more]

PMID: 33726814

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Project description:Transplantation of hematopoietic stem cells (HSCs) from human umbilical cord blood (hUCB) holds great promise for treating a broad spectrum of hematological disorders including cancer. However, the limited number of HSCs in a single hUCB unit restricts its widespread use. Although extensive efforts have led to multiple methods for ex vivo expansion of human HSCs by targeting single molecules or pathways, it remains unknown whether it is possible to simultaneously manipulate the large number of targets essential for stem cell self-renewal. Recent studies indicate that N6-methyladenosine (m6A) modulates the expression of a group of mRNAs critical for stem cell-fate determination by influencing their stability. Among several m6A readers, YTHDF2 is recognized as promoting targeted mRNA decay. However, the physiological functions of YTHDF2 in adult stem cells are unknown. Here we show that following the conditional knockout (KO) of mouse Ythdf2 the numbers of functional HSC were increased without skewing lineage differentiation or leading to hematopoietic malignancies. Furthermore, knockdown (KD) of human YTHDF2 led to more than a 10-fold increase in the ex vivo expansion of hUCB HSCs, a fivefold increase in colony-forming units (CFUs), and more than an eightfold increase in functional hUCB HSCs in the secondary serial of a limiting dilution transplantation assay. Mapping of m6A in RNAs from mouse hematopoietic stem and progenitor cells (HSPCs) as well as from hUCB HSCs revealed its enrichment in mRNAs encoding transcription factors critical for stem cell self-renewal. These m6A-marked mRNAs were recognized by Ythdf2 and underwent decay. In Ythdf2 KO HSPCs and YTHDF2 KD hUCB HSCs, these mRNAs were stabilized, facilitating HSC expansion. Knocking down one of YTHDF2's key targets, Tal1 mRNA, partially rescued the phenotype. Our study provides the first demonstration of the function of YTHDF2 in adult stem cell maintenance and identifies its important role in regulating HSC ex vivo expansion by regulating the stability of multiple mRNAs critical for HSC self-renewal, thus identifying potential for future clinical applications.

Dataset Information

Histone lactylation drives oncogenesis by facilitating m⁶A reader protein YTHDF2 expression in ocular melanoma.

Background

Results

Conclusion

Publications

Histone lactylation drives oncogenesis by facilitating m<sup>6</sup>A reader protein YTHDF2 expression in ocular melanoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma.

Background

Results

Conclusion

Publications

Histone lactylation drives oncogenesis by facilitating m<sup>6</sup>A reader protein YTHDF2 expression in ocular melanoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Histone lactylation drives oncogenesis by facilitating m⁶A reader protein YTHDF2 expression in ocular melanoma.