DNA demethylase ALKBH1 promotes adipogenic differentiation via regulation of HIF-1 signaling

Abstract

DNA N6-adenine methylation (6mA), as a novel adenine modification existing in eukaryotes, shows essential functions in embryogenesis and mitochondrial transcriptions. ALKBH1 is a demethylase of 6mA and plays critical roles in osteogenesis, tumorigenesis, and adaptation to stress. However, the integrated biological functions of ALKBH1 still require further exploration. Here, we demonstrate that knockdown of ALKBH1 inhibits adipogenic differentiation in both human mesenchymal stem cells (hMSCs) and 3T3-L1 preadipocytes, while overexpression of ALKBH1 leads to increased adipogenesis. Using a combination of RNA-seq and N6-mA-DNA-IP-seq analyses, we identify hypoxia-inducible factor-1 (HIF-1) signaling as a crucial downstream target of ALKBH1 activity. Depletion of ALKBH1 leads to hypermethylation of both HIF-1α and its downstream target GYS1. Simultaneous overexpression of HIF-1α and GYS1 restores the adipogenic commitment of ALKBH1-deficient cells. Taken together, our data indicate that ALKBH1 is indispensable for adipogenic differentiation, revealing a novel epigenetic mechanism that regulates adipogenesis. DNA N6-adenine methylation (6mA), as a novel adenine modification existing in eukaryotes, shows essential functions in embryogenesis and mitochondrial transcriptions. ALKBH1 is a demethylase of 6mA and plays critical roles in osteogenesis, tumorigenesis, and adaptation to stress. However, the integrated biological functions of ALKBH1 still require further exploration. Here, we demonstrate that knockdown of ALKBH1 inhibits adipogenic differentiation in both human mesenchymal stem cells (hMSCs) and 3T3-L1 preadipocytes, while overexpression of ALKBH1 leads to increased adipogenesis. Using a combination of RNA-seq and N6-mA-DNA-IP-seq analyses, we identify hypoxia-inducible factor-1 (HIF-1) signaling as a crucial downstream target of ALKBH1 activity. Depletion of ALKBH1 leads to hypermethylation of both HIF-1α and its downstream target GYS1. Simultaneous overexpression of HIF-1α and GYS1 restores the adipogenic commitment of ALKBH1-deficient cells. Taken together, our data indicate that ALKBH1 is indispensable for adipogenic differentiation, revealing a novel epigenetic mechanism that regulates adipogenesis. Mesenchymal stem cells (MSCs) are capable of self-renewal and pluripotent differentiation, which eventually develop into specific types of somatic cells. The appropriate balance on cell fate decisions requires precise regulation of transcriptional and epigenetic networks (1Ambrosi T.H. Scialdone A. Graja A. Gohlke S. Jank A.M. Bocian C. Woelk L. Fan H. Logan D.W. Schurmann A. Saraiva L.R. Schulz T.J. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration.Cell Stem Cell. 2017; 20: 771-784.e6Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar, 2Yin B. Yu F. Wang C. Li B. Liu M. Ye L. Epigenetic control of mesenchymal stem cell fate decision via histone methyltransferase Ash1l.Stem Cells. 2019; 37: 115-127Crossref PubMed Scopus (39) Google Scholar). Under the pathological conditions, an increasing number of cells undergo a shift from osteogenesis to adipogenesis (3Wu Y. Xie L. Wang M. Xiong Q. Guo Y. Liang Y. Li J. Sheng R. Deng P. Wang Y. Zheng R. Jiang Y. Ye L. Chen Q. Zhou X. et al.Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis.Nat. Commun. 2018; 9: 4772Crossref PubMed Scopus (237) Google Scholar, 4Kawai M. Devlin M.J. Rosen C.J. Fat targets for skeletal health.Nat. Rev. Rheumatol. 2009; 5: 365-372Crossref PubMed Scopus (110) Google Scholar), resulting in the accumulation of lipid droplets and various metabolic disorders (5Cristancho A.G. Lazar M.A. Forming functional fat: A growing understanding of adipocyte differentiation.Nat. Rev. Mol. Cell Biol. 2011; 12: 722-734Crossref PubMed Scopus (975) Google Scholar, 6Chen Y. Wang Y. Lin W. Sheng R. Wu Y. Xu R. Zhou C. Yuan Q. AFF1 inhibits adipogenic differentiation via targeting TGM2 transcription.Cell Prolif. 2020; 53: e12831Crossref PubMed Scopus (7) Google Scholar). These changes lead to tissue inflammation, senescence-associated secretory phenotype (SASP), and osteoporosis (5Cristancho A.G. Lazar M.A. Forming functional fat: A growing understanding of adipocyte differentiation.Nat. Rev. Mol. Cell Biol. 2011; 12: 722-734Crossref PubMed Scopus (975) Google Scholar, 7Wang Q. Nie L. Zhao P. Zhou X. Ding Y. Chen Q. Wang Q. Diabetes fuels periodontal lesions via GLUT1-driven macrophage inflammaging.Int. J. Oral Sci. 2021; 13: 11Crossref PubMed Scopus (21) Google Scholar, 8Guan Y. Zhang C. Lyu G. Huang X. Zhang X. Zhuang T. Jia L. Zhang L. Zhang C. Li C. Tao W. Senescence-activated enhancer landscape orchestrates the senescence-associated secretory phenotype in murine fibroblasts.Nucleic Acids Res. 2020; 48: 10909-10923Crossref PubMed Scopus (21) Google Scholar, 9Li Q. Wang M. Xue H. Liu W. Guo Y. Xu R. Shao B. Yuan Q. Ubiquitin-specific protease 34 inhibits osteoclast differentiation by regulating NF-kappaB signaling.J. Bone Miner. Res. 2020; 35: 1597-1608Crossref PubMed Scopus (33) Google Scholar). Extensive efforts have been devoted to elucidating the pluripotency MSCs maintained during differentiation. Although plenty of literatures are trying to determine these phenotypes in various mechanisms, the connection between DNA methylations and pluripotency MSCs remains unclear. Epigenetic regulations mainly refer to DNA methylation, histone modifications, noncoding RNAs, transcription factor binding, and chromatin remodeling (10Skvortsova K. Iovino N. Bogdanovic O. Functions and mechanisms of epigenetic inheritance in animals.Nat. Rev. Mol. Cell Biol. 2018; 19: 774-790Crossref PubMed Scopus (271) Google Scholar, 11Wang Y. Deng P. Liu Y. Wu Y. Chen Y. Guo Y. Zhang S. Zheng X. Zhou L. Liu W. Li Q. Lin W. Qi X. Ou G. Wang C. et al.Alpha-ketoglutarate ameliorates age-related osteoporosis via regulating histone methylations.Nat. Commun. 2020; 11: 5596Crossref PubMed Scopus (90) Google Scholar). These modifications influenced by various stimuli are of paramount importance on cell lineage decisions (12Alvarez-Errico D. Vento-Tormo R. Sieweke M. Ballestar E. Epigenetic control of myeloid cell differentiation, identity and function.Nat. Rev. Immunol. 2015; 15: 7-17Crossref PubMed Scopus (231) Google Scholar, 13Daniunaite K. et al.Epigenetic regulation of human adipose-derived stem cells differentiation.Mol. Cell. Biochem. 2015; 410: 111-120Crossref PubMed Scopus (16) Google Scholar, 14Xu Q. Xie W. Epigenome in early mammalian development: Inheritance, reprogramming and establishment.Trends Cell Biol. 2018; 28: 237-253Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Abnormal methylation leads to tumorigenesis, neuronal development retardation, and metabolic disorders (15Ehrlich M. DNA hypermethylation in disease: Mechanisms and clinical relevance.Epigenetics. 2019; 14: 1141-1163Crossref PubMed Scopus (169) Google Scholar, 16Robertson K.D. DNA methylation and human disease.Nat. Rev. Genet. 2005; 6: 597-610Crossref PubMed Scopus (2192) Google Scholar, 17Zhang L. Silva T.C. Young J.I. Gomez L. Schmidt M.A. Hamilton-Nelson K.L. Kunkle B.W. Chen X. Martin E.R. Wang L. Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer's disease.Nat. Commun. 2020; 11: 6114Crossref PubMed Scopus (36) Google Scholar). Of note, human adipogenesis and osteogenesis are also relevant with DNA methylation alterations across all genomic segments (18Jin Q. Wang C. Kuang X. Feng X. Sartorelli V. Ying H. Ge K. Dent S.Y. Gcn5 and PCAF regulate PPARgamma and Prdm16 expression to facilitate brown adipogenesis.Mol. Cell. Biol. 2014; 34: 3746-3753Crossref PubMed Scopus (48) Google Scholar, 19Zhou C. Liu Y. Li X. Zou J. Zou S. DNA N6-methyladenine demethylase ALKBH1 enhances osteogenic differentiation of human MSCs.Bone Res. 2016; 4: 16033Crossref PubMed Scopus (52) Google Scholar). In recent years, DNA N6-adenine methylation (6mA), enzyme-mediated by N6AMT1 and ALBKH1, has been discovered to affect mammalian development (20Wu T.P. Wang T. Seetin M.G. Lai Y. Zhu S. Lin K. Liu Y. Byrum S.D. Mackintosh S.G. Zhong M. Tackett A. Wang G. Hon L.S. Fang G. Swenberg J.A. et al.DNA methylation on N(6)-adenine in mammalian embryonic stem cells.Nature. 2016; 532: 329-333Crossref PubMed Scopus (445) Google Scholar, 21Xiao C.L. Zhu S. He M. Chen, Zhang Q. Chen Y. Yu G. Liu J. Xie S.Q. Luo F. Liang Wang Wang K. et DNA modification in the human Cell. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). a and has been as a DNA demethylase (20Wu T.P. Wang T. Seetin M.G. Lai Y. Zhu S. Lin K. Liu Y. Byrum S.D. Mackintosh S.G. Zhong M. Tackett A. Wang G. Hon L.S. Fang G. Swenberg J.A. et al.DNA methylation on N(6)-adenine in mammalian embryonic stem cells.Nature. 2016; 532: 329-333Crossref PubMed Scopus (445) Google Scholar). that ALKBH1 the of and of histone R. D. J.A. T. A. T. E. ALKBH1 is a histone in Cells. PubMed Scopus (90) Google Scholar, F. W. Luo G. Wang X. Y. J. Wang X. Q. Zheng G. H. D. M. A. T. et regulates 2016; Full Text Full Text PDF PubMed Scopus Google Scholar, M. S. R. Zhao W. Liu G. Li Liu X. Wu T. A. Li H. ALKBH1 as an demethylase of Res. 2020; PubMed Scopus Google Scholar). of DNA are the of ALKBH1 (20Wu T.P. Wang T. Seetin M.G. Lai Y. Zhu S. Lin K. Liu Y. Byrum S.D. Mackintosh S.G. Zhong M. Tackett A. Wang G. Hon L.S. Fang G. Swenberg J.A. et al.DNA methylation on N(6)-adenine in mammalian embryonic stem cells.Nature. 2016; 532: 329-333Crossref PubMed Scopus (445) Google Scholar, M. S. R. Zhao W. Liu G. Li Liu X. Wu T. A. Li H. ALKBH1 as an demethylase of Res. 2020; PubMed Scopus Google Scholar). 6mA leads to of pluripotency of and differentiation of and in the and R. D. J.A. T. A. T. E. ALKBH1 is a histone in Cells. PubMed Scopus (90) Google Scholar, S. M. D. T. K. C. P. lineage differentiation in PubMed Scopus Google Scholar, J. E. A. R. K. T. A. and PubMed Scopus Google Scholar). that ALKBH1 osteogenic differentiation by 6mA the of C. Liu Y. Li X. Zou J. Zou S. DNA N6-methyladenine demethylase ALKBH1 enhances osteogenic differentiation of human MSCs.Bone Res. 2016; 4: 16033Crossref PubMed Scopus (52) Google Scholar). the of 6mA in human we the between ALKBH1 and which is unclear. In we that ALKBH1 adipogenic differentiation of and 3T3-L1 to accumulation of in ALKBH1 6mA of HIF-1α and GYS1 to a into the of 6mA in differentiation and we of ALKBH1 and the tissue of and that ALKBH1 in the of In we and 3T3-L1 and increased of as as adipogenic essential and and The of ALKBH1 in both cells to from the early of and we ALKBH1 in and the knockdown by The cell ALKBH1 as by cell for the adipogenic differentiation of ALKBH1-deficient by and as as the expression of and we in 3T3-L1 cells and that the cell the adipogenic differentiation of 3T3-L1 cells. The also by and of the expression of adipogenic and we with control that accumulation is increased in with control In the of adipogenic as and in the and of we ALKBH1 in 3T3-L1 cells and increased of and expression of and In we an by control and 3T3-L1 cells into of (1Ambrosi T.H. Scialdone A. Graja A. Gohlke S. Jank A.M. Bocian C. Woelk L. Fan H. Logan D.W. Schurmann A. Saraiva L.R. Schulz T.J. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration.Cell Stem Cell. 2017; 20: 771-784.e6Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar). that the the is and as as the and the of and the increasing of 3T3-L1 cells the we RNA on ALKBH1 knockdown the control cells adipogenic and in The biological functions of ALKBH1 knockdown the and of lipid the of adipogenesis in ALKBH1-deficient also a of hypoxia-inducible factor-1 (HIF-1) ALKBH1 The expression of critical as and as in the In the of in 3T3-L1 cells by and the overexpression of ALKBH1 in 3T3-L1 cells the of as as the expression of and HIF-1α is by in Y. A. H. Huang G. of hypoxia-inducible in Sci. 2019; PubMed Scopus Google Scholar), 3T3-L1 cells in of to a expression of HIF-1α and its downstream targets both on and A and while overexpression of ALKBH1 the and In we a to the 3T3-L1 with for to and the by the of with our knockdown of the of targets as as expression of and of ALKBH1 the and In we 3T3-L1 cells with the which the of However, knockdown of A of in we to ALKBH1 as a DNA 6mA demethylase by DNA Depletion of increased the 6mA in genomic while overexpression of ALKBH1 6mA modifications in 3T3-L1 cells the N6-mA-DNA-IP-seq we that a and specific 6mA in embryonic stem cells we that the of ALKBH1 and its In we 3T3-L1 cells with HIF-1α and to the functional overexpression of HIF-1α increased the of lipid droplets with the knockdown by the of and and of the adipogenic and in the also of that ALKBH1 regulate our RNA-seq data with N6-mA-DNA-IP-seq data we also that a downstream target of a of DNA 6mA modification the knockdown of The of ALKBH1 the of in 3T3-L1 cells The of GYS1 by the of ALKBH1 both in and that GYS1 target of ALKBH1 in adipogenic differentiation. of GYS1 to the of of and and of adipogenic in 3T3-L1 cells. we HIF-1α and GYS1 and in cells. with cells that of the of lipid droplets in as as the adipogenic to the expression of and increased in cells HIF-1α and GYS1 of adipogenic In ALKBH1 DNA 6mA of both and which to adipogenic differentiation of 3T3-L1 cells. DNA and 6mA in eukaryotes, is of paramount importance to its on embryonic development and metabolic D. The roles of DNA methylation in mammalian development and disease.Nat. Rev. Mol. Cell Biol. 2019; 20: PubMed Scopus Google Scholar). in 6mA leads to and human as B. Y. Wang Li Y. Chen L. Huang L. Zhang W. Chen D. Wu H. B. P. DNA N6-methyladenine is in the Commun. 2017; PubMed Scopus Google Scholar), L. Liu Lin H. D. Tao Q. Liu F. Epigenetic regulation of by DNA J. 2017; PubMed Scopus Google Scholar), C. R. Huang T. Shao Y. Ding W. Wang Y. Jia G. He C. Li He A. Liu Y. is a epigenetic for mitochondrial Cell Biol. 2019; PubMed Scopus Google Scholar), and C.L. Zhu S. He M. Chen, Zhang Q. Chen Y. Yu G. Liu J. Xie S.Q. Luo F. Liang Wang Wang K. et DNA modification in the human Cell. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, Q. Wu T.P. Li Wu Q. Yu Y. Wang P. Wang Y. Zhang C. Lin K. C. Y. et DNA modification in 2018; Full Text Full Text PDF PubMed Scopus Google Scholar). In recent years, which functions as a DNA 6mA has a in embryogenesis and differentiation. of ALKBH1 in in the and cell pluripotency and differentiation C. Liu Y. Li X. Zou J. Zou S. DNA N6-methyladenine demethylase ALKBH1 enhances osteogenic differentiation of human MSCs.Bone Res. 2016; 4: 16033Crossref PubMed Scopus (52) Google Scholar, S. M. D. T. K. C. P. lineage differentiation in PubMed Scopus Google Scholar, J. E. A. R. K. T. A. and PubMed Scopus Google Scholar). In the we the between ALKBH1 and cell adipogenic differentiation. Depletion of ALKBH1 in human MSCs and 3T3-L1 adipogenesis. the overexpression of ALKBH1 leads to lipid droplets accumulation in and tissue in with our ALKBH1 has a crucial in cell fate C. Liu Y. Li X. Zou J. Zou S. DNA N6-methyladenine demethylase ALKBH1 enhances osteogenic differentiation of human MSCs.Bone Res. 2016; 4: 16033Crossref PubMed Scopus (52) Google Scholar). that ALKBH1 the signaling to adipogenesis in and of a functional and a in is in to and inhibits via regulation of Cell. 28: Full Text Full Text PDF PubMed Scopus Google Scholar). the of is from by and factor and of in A. K. A. A. K. B. J. N. A. E. G. J. et of from cells expression of and of to and 2020; Full Text Full Text PDF PubMed Scopus Google Scholar, for Rev. PubMed Scopus Google Scholar, A. with of Rev. 2011; PubMed Scopus Google Scholar). of leads to metabolic as mitochondrial and Wu T. X. Zhu P. C. X. Lin Zhang L.S. Y. L. Zhu A. Liu J. et methylation in mammalian mitochondrial Cell. 2020; Full Text Full Text PDF PubMed Scopus Google Scholar, K. N. J. S. T. of human and PubMed Scopus Google Scholar). A growing number of that during accumulation in to increased O. R. S. Chen A. H. A. O. adipocyte and in 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). HIF-1α with a of S. M. C. B. of in brown by 2017; PubMed Scopus Google Scholar), and R. D. S. Q. A. H. N. obesity by brown tissue Mol. 2017; PubMed Scopus Google Scholar, P. Wang B. in A for the of tissue in J. PubMed Scopus Google Scholar, H. T. E. M. R. T. J. R. K. plays a critical in obesity and PubMed Scopus Google Scholar, C. A. T. T. W. O. of hypoxia-inducible factor in and in 2011; PubMed Scopus Google Scholar). overexpression of HIF-1α in the obesity and with and of tissue C. P. T. R. M. F. Y. S. signaling in 2009; PubMed Scopus Google Scholar, N. T. S. Wang S. S. factor and in Cell. Biol. 2009; PubMed Scopus Google Scholar, A. A. A. T. K. S. A. S. K. M. Y. Y. Y. K. K. et in myeloid cells tissue remodeling 2016; PubMed Scopus Google Scholar). The between ALKBH1 and the in by et and Xie et C.L. Zhu S. He M. Chen, Zhang Q. Chen Y. Yu G. Liu J. Xie S.Q. Luo F. Liang Wang Wang K. et DNA modification in the human Cell. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, Q. Wu T.P. Li Wu Q. Yu Y. Wang P. Wang Y. Zhang C. Lin K. C. Y. et DNA modification in 2018; Full Text Full Text PDF PubMed Scopus Google also our on adipogenesis. In recent years, to the regulations of HIF-1α to The regulations of HIF-1α are these years, the transcription of DNA and regulation of is are However, in pathological conditions, as in and HIF-1α is to epigenetic The of methylation on HIF-1α the transcription and regulates the downstream In ALKBH1 knockdown the DNA methylation of 6mA and the signaling to the hypermethylation of HIF-1α and GYS1. of HIF-1α and to adipogenic differentiation C. A. T. T. W. O. of hypoxia-inducible factor in and in 2011; PubMed Scopus Google Scholar). of HIF-1α the for mechanism is that expression of HIF-1α signaling and the of a crucial that the from metabolic C. Li F. A. O. factor regulates a in Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. K. A. S. M. T. T. T. M. of on of signaling mechanisms for its on and PubMed Scopus Google Scholar). to the of cell and of to obesity with tissue Rev. 2017; 13: PubMed Scopus Google Scholar, mechanisms obesity and metabolic 2017; PubMed Scopus Google Scholar, M. C. Zhang Q. B. L. Zhao S. Wu Y. D.W. signaling in Stem Cell. 2021; 28: Full Text Full Text PDF PubMed Scopus (39) Google Scholar). of HIF-1α also to obesity and and in Rev. 2019; 15: PubMed Scopus Google Scholar, M. P. S. of adipocyte and in 2019; PubMed Scopus Google Scholar). However, ALKBH1 has on the of HIF-1α further downstream of is the in the and in the and E. K. M.G. C. G. H. Li A. via and in Full Text Full Text PDF PubMed Scopus Google Scholar, J. G. P. S. J. is in by the hypoxia-inducible factor and cell PubMed Scopus Google Scholar). of GYS1 in types of factor signaling Huang Huang X. He Y. GYS1 accumulation and via the NF-kappaB in cell 2020; PubMed Scopus Google and signaling to and of cells H. T. K. T. S. K. A of the is with in the PubMed Scopus (33) Google Scholar, K. Huang A.M. B.W. B. W. J. J. S. and with in 2016; 5: PubMed Scopus Google Scholar, in 2005; PubMed Scopus Google Scholar). expression of GYS1 is also to the obesity phenotype in the mechanism remains we that GYS1 is also a target of that GYS1 further adipogenesis by in and signaling ALKBH1 discovered as a DNA 6mA demethylase to in epigenetic networks (20Wu T.P. Wang T. Seetin M.G. Lai Y. Zhu S. Lin K. Liu Y. Byrum S.D. Mackintosh S.G. Zhong M. Tackett A. Wang G. Hon L.S. Fang G. Swenberg J.A. et al.DNA methylation on N(6)-adenine in mammalian embryonic stem cells.Nature. 2016; 532: 329-333Crossref PubMed Scopus (445) Google and to a demethylase on F. W. Luo G. Wang X. Y. J. Wang X. Q. Zheng G. H. D. M. A. T. et regulates 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). He et that the of ALKBH1 and a number of the of 6mA in eukaryotes, its on cell differentiation C. Liu Y. Li X. Zou J. Zou S. DNA N6-methyladenine demethylase ALKBH1 enhances osteogenic differentiation of human MSCs.Bone Res. 2016; 4: 16033Crossref PubMed Scopus (52) Google Scholar), C.L. Zhu S. He M. Chen, Zhang Q. Chen Y. Yu G. Liu J. Xie S.Q. Luo F. Liang Wang Wang K. et DNA modification in the human Cell. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar, Q. Wu T.P. Li Wu Q. Yu Y. Wang P. Wang Y. Zhang C. Lin K. C. Y. et DNA modification in 2018; Full Text Full Text PDF PubMed Scopus Google Scholar), and C. R. Huang T. Shao Y. Ding W. Wang Y. Jia G. He C. Li He A. Liu Y. is a epigenetic for mitochondrial Cell Biol. 2019; PubMed Scopus Google Scholar). Of note, 6mA in that ALKBH1 demethylase DNA RNA and the M. S. R. Zhao W. Liu G. Li Liu X. Wu T. A. Li H. ALKBH1 as an demethylase of Res. 2020; PubMed Scopus Google Scholar). regulates processes both and B. T. P. T. in and 2019; Scopus Google Scholar, by The of the Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). are various from to and of J. Mechanisms of for Rev. 2019; 15: PubMed Scopus Google Scholar). signaling mainly by and various by regulates stem cell differentiation, and mitochondrial functions the P. and adipocyte for tissue in Rev. 2014; 34: PubMed Scopus Google Scholar, factor of mitochondrial and of 2011; PubMed Scopus Google Scholar, stem cells to stem the Cell Biol. PubMed Scopus Google Scholar). has on tissue and and the to Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, in and Full Text Full Text PDF PubMed Scopus Google Scholar). The of novel mechanisms is critical for In we the crucial of DNA 6mA modification on adipogenesis. The combination of of the between ALKBH1 and signaling for the and on the regulations of adipogenesis. mesenchymal stem cells (hMSCs) and 3T3-L1 cell from in with and in a of adipogenic differentiation, cells in and with adipogenic and from for human ALKBH1 and control from by into for A and into for B. we A to and the for to the cells to to of in cells for The knockdown by of the and by with an as in to and with a The with into for The of we for to to cell HIF-1α and GYS1 also from and in the The of by Cell to cell with in and and a of into and of to and for The by a RNA by and to and by with of a by with are in we the to the and on an to control the of and the to expression with in our for the in in and data by K. in RNA-seq in for Mol. Biol. 2021; PubMed Scopus Google Scholar). by on to for and for in the by and to by a The with for and with S. Sheng R. Qi X. Wang J. Guo Y. Yuan Q. regulates by J. Oral Sci. 2021; 13: PubMed Scopus Google Scholar). The The in signaling and with for cells with for with and with for to Y. Yuan Q. L. X. Li J. Yu Y. Liu W. H. Lin P. C. K. Wang obesity and metabolic Sci. S. A. 2018; PubMed Scopus Google Scholar). with and of in of to the droplets the tissue the tissue and with for and by from the and for and 3T3-L1 cells ALKBH1 in into the of (1Ambrosi T.H. Scialdone A. Graja A. Gohlke S. Jank A.M. Bocian C. Woelk L. Fan H. Logan D.W. Schurmann A. Saraiva L.R. Schulz T.J. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration.Cell Stem Cell. 2017; 20: 771-784.e6Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar). and of a by the on and of Fat and in the for and and in D. Zhang S. Wang J. Li Q. Xue H. Sheng R. Xiong Q. Qi X. J. Fan Y. Zhou Yuan Q. stem cells are essential for bone Res. 2020; PubMed Scopus Google Scholar). with and the in for in for with and of and of by for by The by and by DNA with a DNA and for in on the and for in for with The with for and with an of DNA the with in C. Liu Y. Li X. Zou J. Zou S. DNA N6-methyladenine demethylase ALKBH1 enhances osteogenic differentiation of human MSCs.Bone Res. 2016; 4: 16033Crossref PubMed Scopus (52) Google Scholar). The data in in Wu et (20Wu T.P. Wang T. Seetin M.G. Lai Y. Zhu S. Lin K. Liu Y. Byrum S.D. Mackintosh S.G. Zhong M. Tackett A. Wang G. Hon L.S. Fang G. Swenberg J.A. et al.DNA methylation on N(6)-adenine in mammalian embryonic stem cells.Nature. 2016; 532: 329-333Crossref PubMed Scopus (445) Google with the number these data on a for of genomic to the 6mA between the control and the H. W. M. G. 2011; PubMed Scopus Google Scholar). The via an and Y. Q. Wu Xu R. Zou S. Zhou C. enhances differentiation of human Res. Commun. 2020; PubMed Scopus Google Scholar). a as control and a ALKBH1 for the and DNA by The to identify the target The are in to the data and differences by for between by of by the for to The RNA-seq data have been and in the The that have of with the of for with by from the and of Oral L. Y. and Y. Q. L. Y. and Lin Liu and Y. Q. L. C. J. and G. Y. L. Wang J. Wu and L. Q. Y. Q. L. C. and Y. Q. L. Y. and Lin Y. Q. Y. Q. L. Y. L. Wang Wu L. G. and Liu and with

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