Emerging discoveries about undocumented acyltransferase activities of known histone acetyltransferases(HATs)advance our understandings in the regulation of histone modifications.However,the molecular basis of HATs selecting acyl coenzyme A(acyl-CoA)substrates for histone modification is less known.We here report that lysine acetyltransferase 2A(KAT2A)as an illustrative instance of HATs can selectively utilize acetyl-CoA,propionyl-CoA,butyryl-CoA,and succinyl-CoA to directly deposit 18 histone acylation hallmarks in nucleosome.By analyzing the co-crystal structures of the catalytic domain of KAT2A in complex with acetyl-CoA,propionyl-CoA,butyryl-CoA,malonyl-CoA,succinyl-CoA,and glutaryl-CoA,we conclude that the alternative substrate-binding pocket of KAT2A and the length and electrostatic features of the acyl chain cooperatively determine the selection of the acyl-CoA substrates by KAT2A.This study reveals the molecular basis underlying the pluripotency of HATs that selectively install acylation hallmarks in nucleosomes,which might serve as instrumental mechanism to precisely regulate histone acylation profiles in cells.
Sha LiNan LiJie HeRunxin ZhouZhimin LuYizhi Jane TaoYusong R.GuoYugang Wang
Emerging discoveries about undocumented acyltransferase activities of known histone acetyltransferases(HATs)advance our understandings in the regulation of histone modifications.However,the molecular basis of HATs selecting acyl coenzyme A(acyl-CoA)substrates for histone modification is less known.We here report that lysine acetyltransferase 2A(KAT2A)as an illustrative instance of HATs can selectively utilize acetyl-CoA,propionyl-CoA,butyryl-CoA,and succinyl-CoA to directly deposit 18 histone acylation hallmarks in nucleosome.By analyzing the co-crystal structures of the catalytic domain of KAT2A in complex with acetyl-CoA,propionyl-CoA,butyryl-CoA,malonyl-CoA,succinyl-CoA,and glutaryl-CoA,we conclude that the alternative substrate-binding pocket of KAT2A and the length and electrostatic features of the acyl chain cooperatively determine the selection of the acyl-CoA substrates by KAT2A.This study reveals the molecular basis underlying the pluripotency of HATs that selectively install acylation hallmarks in nucleosomes,which might serve as instrumental mechanism to precisely regulate histone acylation profiles in cells.
Sha LiNan LiJie HeRunxin ZhouZhimin LuYizhi Jane TaoYusong R.GuoYugang Wang
Hematopoiesis requires finely tuned regulation of gene expression at each stage of development.The regulation of gene transcription involves not only individual transcription factors(TFs)but also transcription complexes(TCs)composed of transcription factor(s)and multisubunit cofactors.In their normal compositions,TCs orchestrate lineage-specific patterns of gene expression and ensure the production of the correct proportions of individual cell lineages during hematopoiesis.The integration of posttranslational and conformational modifcations in the chromatin landscape,nucleosomes,histones and interacting components via the cofactor-TF interplay is critical to optimal TF activity.Mutations or translocations of cofactor genes are expected to alter cofactor-TF interactions,which may be causative for the pathogenesis of various hematologic disorders.Blocking TF oncogenic activity in hematologic disorders through targeting cofactors in aberrant complexes has been an exciting therapeutic strategy.In this review,we summarize the current knowledge regarding the models and functions of cofactor-TF interplay in physiological hematopoiesis and highlight their implications in the etiology of hematological malignancies.This review presents a deep insight into the physiological and pathological implications of transcription machinery in the blood system.
Zi WangPan WangYanan LiHongling PengYu ZhuNarla MohandasJing Liu
Introduction: High grade dysplasia of the cervix has a high incidence and can progress to cervical cancer. The aim was to study cofactors associated with high-grade cervical dysplasia. Methodology: This was a retrospective case-control study without matching. Women with high grade dysplasia were the cases while those with a normal screening test represented the controls. The study took place at the Gabriel Touré University Hospital Center in Bamako. We included 351 cases and 420 controls. The capture and analysis were performed using the SPSS 20 software. A univariate and multivariate logistic regression analysis was performed for the analysis of risk cofactors. The statistical tests used were the odds ratio and its confidence interval and the statistical significance threshold was set at p Results: In univariate analysis, the co-factors statistically significantly associated with the occurrence of high-grade dysplasia were parity 0.6 (0.5 - 0.9), gestational 0.7 (0.5 - 0.9), smoking of the spouse 3.4 (1.1 - 11.3), the non-schooling 1.4 (1.2 - 2.1). In multivariate analysis after adjusting for confounding factors, two co-factors have significantly increased the risk of high-grade dysplasia: lack of schooling 1.4 (1.2 - 2.0) and polygamy 1.5 (1.4 - 2.5). Conclusion: At the end of this study, polygamy and lack of schooling were the main risk factors. The prevention of cervical cancer will go through the education of girls and women as well as communication for behavioral change and social change.
