TET蛋白家族与5-羟甲基胞嘧啶在干细胞及再生医学表观遗传调控中的作用

Roles of ten eleven translocation proteins family and 5-hydroxymethylcytosine in epigenetic regulation of stem cells and regenerative medicine

表观遗传调控是对DNA及组蛋白的修饰,决定了何时、何地、以何种方式对遗传信息进行表达[1]。DNA甲基化是目前研究最多的表观遗传调控方式之一[2],将一个甲基共价结合在DNA胞嘧啶的5-碳位置上形成5-甲基胞嘧啶(5-methylcytosine,5mC)。过去人们曾认为DNA甲基化是一个不可逆的过程,只能通过DNA复制过程来被动稀释,但近年来对TET(ten eleven translocation)蛋白的研究发现,TET蛋白家族可以催化5mC氧化生成5-羟甲基胞嘧啶(5-hydroxymethylcytosine,5hmC)、5-甲酰胞嘧啶(5-formylcytosine,5fC)和5-羧基胞嘧啶(5-carboxylcytosine,5caC),从而消除DNA甲基化印记,促进“主动”DNA去甲基化过程[3]。

The methylation of cytosine is one of the most fundamental epigenetic modifications in mammalian genomes,and is involved in multiple crucial processes including gene expression,cell differentiation,embryo development and oncogenesis.In the past,DNA methylation was thought to be an irreversible process,which could only be diluted passively through DNA replication.It is now becoming increa-singly obvious that DNA demethylation can be an active process and plays a crucial role in biological processes.Ten eleven translocation(TET)proteins are the key factors modulating DNA demethylation.This family contains three members:TET1,TET2 and TET3.Although three TET proteins have relatively conserved catalytic domains,their roles in organisms are not repeated,and their expression has significant cell/organ specificity.TET1 is mainly expressed in embryonic stem cells,TET2 is mainly expressed in hematopoietic system,and TET3 is widely expressed in cerebellum,cortex and hippocampus.This family catalyzes 5-methylcytosine to 5-hydroxymethylcytosine and other oxidative products,reactivates silenced-gene expression,in turn maintains stem cell pluripotency and regulates lineage specification.With the development of tissue engineering,organ transplantation,autologous tissue transplantation and artificial prosthesis have been widely used in clinical treatment,but these technologies have limitations.Regenerative medicine,which uses stem cells and stem cell related factors for treatment,may provide alternative therapeutic strategies for multiple diseases.Among all kinds of human stem cells,adipose-derived stem cells(ADSCs)are the most prospective stem cell lineage since they have no ethical issues and can be easily obtained with large quantities.To date,ADSCs have been shown to have strong proli-feration capacity,secrete numerous soluble factors and have multipotent differentiation ability.However,the underlying mechanism of the proliferation,secretion,acquired pluripotency,and lineage specific differentiation of ADSCs are still largely unknown.Some studies have explored the role of epigenetic regulation and TET protein in embryonic stem cells,but little is known about its role in ADSCs.By studying the roles of TET proteins and 5-hydroxymethylcytosine in ADSCs,we could provide new theoretical foundation for the clinical application of ADSCs and the stem cell-based therapy.In the future,combined with bioprinting technology,ADSCs may be used in tissue and organ regeneration,plastic surgery reconstruction and other broader fields.