본문 바로가기
KERD
논문KCI 등재

SMC3 contributes to heart development by regulating super-enhancer associated genes

Zhang Bowen|Zhu Yongchang|Zhang Zhen|Wu Feizhen|Ma Xiaojing|Sheng Wei|Dai Ranran|Guo Zhenglong|Yan Weili|Hao Lili|Huang Guoying|Ma Duan|Hao Bingtao|Ma Jing
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2024.12|Experimental and Molecular Medicine|제56권 |pp. 1826-1842|DOI 10.1038/s12276-024-01293-0

1

조회

0

다운로드

0

인용

0

참고문헌

주제분류생화학

초록

Abnormal cardiac development has been observed in individuals with Cornelia de Lange syndrome (CdLS) due to mutations in genes encoding members of the cohesin complex. However, the precise role of cohesin in heart development remains elusive. In this study, we aimed to elucidate the indispensable role of SMC3, a component of the cohesin complex, in cardiac development and its underlying mechanism. Our investigation revealed that CdLS patients with SMC3 mutations have high rates of congenital heart disease (CHD). We utilized heart-specific Smc3-knockout (SMC3-cKO) mice, which exhibit varying degrees of outflow tract (OFT) abnormalities, to further explore this relationship. Additionally, we identified 16 rare SMC3 variants with potential pathogenicity in individuals with isolated CHD. By employing single-nucleus RNA sequencing and chromosome conformation capture high-throughput genome-wide translocation sequencing, we revealed that Smc3 deletion downregulates the expression of key genes, including Ets2, in OFT cardiac muscle cells by specifically decreasing interactions between super-enhancers (SEs) and promoters. Notably, Ets2-SE-null mice also exhibit delayed OFT development in the heart. Our research revealed a novel role for SMC3 in heart development via the regulation of SE-associated genes, suggesting its potential relevance as a CHD-related gene and providing crucial insights into the molecular basis of cardiac development.

Abstract

Abnormal cardiac development has been observed in individuals with Cornelia de Lange syndrome (CdLS) due to mutations in genes encoding members of the cohesin complex. However, the precise role of cohesin in heart development remains elusive. In this study, we aimed to elucidate the indispensable role of SMC3, a component of the cohesin complex, in cardiac development and its underlying mechanism. Our investigation revealed that CdLS patients with SMC3 mutations have high rates of congenital heart disease (CHD). We utilized heart-specific Smc3-knockout (SMC3-cKO) mice, which exhibit varying degrees of outflow tract (OFT) abnormalities, to further explore this relationship. Additionally, we identified 16 rare SMC3 variants with potential pathogenicity in individuals with isolated CHD. By employing single-nucleus RNA sequencing and chromosome conformation capture high-throughput genome-wide translocation sequencing, we revealed that Smc3 deletion downregulates the expression of key genes, including Ets2, in OFT cardiac muscle cells by specifically decreasing interactions between super-enhancers (SEs) and promoters. Notably, Ets2-SE-null mice also exhibit delayed OFT development in the heart. Our research revealed a novel role for SMC3 in heart development via the regulation of SE-associated genes, suggesting its potential relevance as a CHD-related gene and providing crucial insights into the molecular basis of cardiac development.

참고문헌 (65)

  1. Boyd, R., "Environmental exposures and con genital heart disease", Pediatrics, 149, pp.e2021052151~ (2022)
  2. Galdos, F. X., "Cardiac regeneration : lessons from development", Circ. Res, 120, pp.941~959 (2017)
  3. Rammah, M., "PPARγ and NOTCH regulate regional identity in the murine cardiac outflow tract", Circ. Res, 131, pp.842~858 (2022)
  4. Chapman, G., "Functional genomics and gene-environment interaction highlight the complexity of congenital heart disease caused by Notch pathway variants", Hum. Mol. Genet, 29, pp.566~579 (2020)
  5. Whyte, W. A., "Master transcription factors and mediator establish super enhancers at key cell identity genes", Cell, 153, pp.307~319 (2013)
  6. Feng, D., "Chromatin organizer SATB1 controls the cell identity of CD4(+)CD8(+)double-positive thymocytes by regulating the activity of super enhancers", Nat. Commun, 13, pp.5554~ (2022)
  7. Borck, P. C., "BET epigenetic reader proteins in cardio vascular transcriptional programs", Circ. Res, 126, pp.1190~1208 (2020)
  8. Dey, A., "BRD4 directs hematopoietic stem cell development and modulates macrophage inflammatory responses", Embo j, 38, pp.e100293~ (2019)
  9. Man, J. C. K., "Genetic dissection of a super enhancer controlling the Nppa Nppb cluster in the heart", Circ. Res, 128, pp.115~129 (2021)
  10. Hnisz, D., "Super-enhancers in the control of cell identity and disease", Cell, 155, pp.934~947 (2013)
  11. Vos, E. S. M., "Interplay between CTCF boundaries and a super enhancer controls cohesin extrusion trajectories and gene expression", Mol. Cell, 81, pp.3082~3095 (2021)
  12. Eagen, K. P., "Principles of chromosome architecture revealed by Hi-C", Trends Biochem Sci, 43, pp.469~478 (2018)
  13. Rao, S. S. P., "Cohesin loss eliminates all loop domains", Cell, 171, pp.305~320 (2017)
  14. Sarogni, P., "Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach", J. Med Genet, 57, pp.289~295 (2020)
  15. Panarotto, M., "Cornelia de Lange syndrome mutations in NIPBL can impair cohesin-mediated DNA loop extrusion", Proc. Natl Acad. Sci. USA, 119, pp.e2201029119~ (2022)
  16. Singh, V. P., "Cohesin and human disease : lessons from mouse models", Curr. Opin. Cell Biol, 37, pp.9~17 (2015)
  17. Chatfield, K. C., "Congenital heart disease in Cornelia de Lange syndrome:phenotype and genotype analysis", Am. J. Med Genet A, 158a, pp.2499~2505 (2012)
  18. Santos, R., "Conditional Creation and Rescue of Nipbl-Deficiency in Mice Reveals Multiple Determinants of Risk for Congenital Heart Defects", PLoS Biol, 14, pp.e2000197~ (2016)
  19. Muto, A., "Multifactorial origins of heart and gut defects in nipbl-deficient zebrafish, a model of Cornelia de Lange Syn drome", PLoS Biol, 9, pp.e1001181~ (2011)
  20. Hao, L., "WDR62 variants contribute to congenital heart disease by inhibiting cardiomyocyte proliferation", Clin. Transl. Med, 12, pp.e941~ (2022)
  21. Ayerza Casas, A., "Cornelia de Lange syndrome: congenital heart disease in 149 patients", Med Clin. (Barc.), 149, pp.300~302 (2017)
  22. Kline, A. D., "Diagnosis and management of Cornelia de Lange syndrome : first international consensus statement", Nat. Rev. Genet, 19, pp.649~666 (2018)
  23. Ishiguro, K. I., "The cohesin complex in mammalian meiosis", Genes Cells, 24, pp.6~30 (2019)
  24. Watrin, E., "Gene regulation and chromatin organization : relevance of cohesin mutations to human disease", Curr. Opin. Genet Dev, 37, pp.59~66 (2016)
  25. Pistocchi, A., "Cornelia de Lange Syndrome : NIPBL haploinsufficiency downregulates canonical Wnt pathway in zebrafish embryos and patients f ibroblasts", Cell Death Dis, 4, pp.e866~ (2013)
  26. Gil-Rodríguez, M. C., "De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes", Hum. Mutat, 36, pp.454~462 (2015)
  27. Mannini, L., "Mutation spectrum and genotype-phenotype correlation in Cornelia de Lange syndrome", Hum. Mutat, 34, pp.1589~1596 (2013)
  28. Ansari, M., "Genetic heterogeneity in Cornelia de Lange syndrome(CdLS)and CdLS-like phenotypes with observed and predicted levels of mosaicism", J. Med Genet, 51, pp.659~668 (2014)
  29. Yuan, B., "Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes", J. Clin. Invest, 125, pp.636~651 (2015)
  30. Liu, C., "Analysis of clinical and genetic characteristics in 10 Chinese indivi duals with Cornelia de Lange syndrome and literature review", Mol. Genet Genom. Med, 8, pp.e1471~ (2020)
  31. Li, R., "A Chinese Case of Cornelia de Lange Syndrome Caused by a Patho genic Variant in SMC3 and a Literature Review", Front Endocrinol, 12, pp.604500~ (2021)
  32. Ma, J., "Hypermethylation-mediated down-regulation of lncRNA TBX5-AS1 : 2in Tetralogy of Fallot inhibits cell proliferation by reducing TBX5 expression", J. Cell Mol. Med, 24, pp.6472~6484 (2020)
  33. Hu, P., "Single-nucleus transcriptomic survey of cell diversity and functional maturation in postnatal mammalian hearts", Genes Dev, 32, pp.1344~1357 (2018)
  34. Wolfien, M., "Single-Nucleus Sequencing of an Entire Mammalian Heart : Cell Type Composition and Velocity", Cells, 9, pp.318~ (2020)
  35. Liu, X., "Single-Cell RNA-Seq of the Developing Cardiac Outflow Tract Reveals Convergent Development of the Vascular Smooth Muscle Cells", Cell Rep, 28, pp.1346~1361 (2019)
  36. Hill, M. C., "A cellular atlas of Pitx2-dependent cardiac development", Devel opment, 146, pp.dev180398~ (2019)
  37. Feng, W., "Single-cell transcriptomic analysis identifies murine heart mole cular features at embryonic and neonatal stages", Nat. Commun, 13, pp.7960~ (2022)
  38. Kitagawa, Y., "Guidance of regulatory T cell development by Satb1dependent super-enhancer establishment", Nat. Immunol, 18, pp.173~183 (2017)
  39. Gartlgruber, M., "Super enhancers define regulatory subtypes and cell identity in neuroblastoma", Nat. Cancer, 2, pp.114~128 (2021)
  40. Sengupta, S., "Super-Enhancer-Driven Transcriptional Dependen cies in Cancer", Trends Cancer, 3, pp.269~281 (2017)
  41. Nishiyama, T., "Cohesion and cohesin-dependent chromatin organization", Curr. Opin. Cell Biol, 58, pp.8~14 (2019)
  42. Niessen, K., "Notch signaling in cardiac development", Circ. Res, 102, pp.1169~1181 (2008)
  43. Islas, J. F., "Transcription factors ETS2 and MESP1 transdifferentiate human dermal fibroblasts into cardiac progenitors", Proc. Natl Acad. Sci. USA, 109, pp.13016~13021 (2012)
  44. Lie-Venema, H., "Ets-1 and Ets-2 transcription factors are essential for normal coronary and myocardial development in chicken embryos", Circ. Res, 92, pp.749~756 (2003)
  45. Kagey, M. H., "Mediator and cohesin connect gene expression and chromatin architecture", Nature, 467, pp.430~435 (2010)
  46. Matthews, B. J., "Computational prediction of CTCF", cohesin-based intra-TAD loops that insulate chromatin contacts and gene expression in mouse liver, 2018, pp.7, e34077~
  47. Brown, J. M., "A tissue-specific self-interacting chromatin domain forms independently of enhancer-promoter interactions", Nat. Commun, 9, pp.3849~ (2018)
  48. Cheng, N., "STAG2 promotes the myelination transcriptional program in oligodendrocytes", Elife, 11, pp.e77848~ (2022)
  49. Yamamoto, H., "Defective trophoblast function in mice with a targeted mutation of Ets2", Genes Dev, 12, pp.1315~1326 (1998)
  50. Cohen, E. D., "Wnt5a and Wnt11are essential for second heart field progenitor development", Development, 139, pp.1931~1940 (2012)
  51. Touma, M., "Wnt11 regulates cardiac chamber development and disease during perinatal maturation", JCI Insight, 2, pp.e94904~ (2017)
  52. Wu, S. P., "Tbx18 regulates development of the epicardium and coronary vessels", Dev. Biol, 383, pp.307~320 (2013)
  53. Varadkar, P., "Notch2 is required for the proliferation of cardiac neural crest derived smooth muscle cells", Dev. Dyn, 237, pp.1144~1152 (2008)
  54. McCright, B., "A mouse model of Alagille syndrome : Notch2as a genetic modifier of Jag1 haploinsufficiency", Development, 129, pp.1075~1082 (2002)
  55. Ristevski, S., "Ets2 is expressed during mor phogenesis of the somite and limb in the mouse embryo", Mech. Dev, 116, pp.165~168 (2002)
  56. Bosman, A., "Perturbations of heart development and function in cardio myocytes from human embryonic stem cells with trisomy 21", Stem Cells, 33, pp.1434~1446 (2015)
  57. Piroddi, N., "Myocardial overexpression of ANKRD1 causes sinus venosus defects and progressive diastolic dysfunction", Cardiovasc Res, 116, pp.1458~1472 (2020)
  58. Iwahana, T., "Novel myocardial markers GADD45G and NDUFS5 identified by RNA-sequencing predicts left ventricular reverse remodeling in advanced non ischemic heart failure : a retrospective cohort study", BMC Cardiovasc Disord, 20, pp.116~ (2020)
  59. Lucas, A., "Gadd45γ regulates cardiomyocyte death and post-myocardial infarction left ventricular remodelling", Cardiovasc Res, 108, pp.254~267 (2015)
  60. Rathod, R. H., "Myocardial Fibrosis in Congenital Heart Disease", Circ. J, 80, pp.1300~1307 (2016)
  61. Hu, C., "MicroRNA-219-5p participates in cyanotic congenital heart disease progression by regulating cardiomyocyte apoptosis", Exp. Ther. Med, 21, pp.36~ (2021)
  62. Dwyer, J., "Transcriptional regulation of telomerase activity : roles of the the Ets transcription factor family", Ann. N. Y Acad. Sci, 1114, pp.36~47 (2007)
  63. Haridhasapavalan, K. K., "Codon Opti mization, Cloning, Expression, Purification, and Secondary Structure Determina tion of Human ETS2 Transcription Factor", Mol. Biotechnol, 62, pp.485~494 (2020)
  64. Li, J., "ETS2 and microRNA-155 regulate the pathogenesis of heart failure through targeting and regulating GPR18 expression", Exp. Ther. Med, 19, pp.3469~3478 (2020)
  65. Luo, Y., "Cooperative Binding of ETS2 and NFAT Links Erk1", 2 and Calcineurin Signaling in the Pathogenesis of Cardiac Hypertrophy, 2021, pp.144, 34~51

관련 논문AI추천

Novel Pathogenic Variant (c.3178G>A) in the SMC1A Gene in a Family With Cornelia de Lange Syndrome Identified by Exome Sequencing기창석, 김진경, 이창우, 장미애대한진단검사의학회 · Annals of Laboratory Medicine2015 · 제35권 제6호Tissue-specific lncRNA GATA6-AS1 and its ortholog Moshe as essential regulators of aortic valve developmentChae-Yi Kim, Eun-Hye Moon, Han-Se Kim, Hyeon Myeong Kim, Jasmin E. Turner, Je-Yoel Cho, Ji Hoon Oh, Na-Jung Kim, Su Haeng Sung, Yeo-Jin Im, Yong Jun Kim, Young Jae Lee생화학분자생물학회 · BMB Reports2025 · 제58권 제4호α-Kleisin subunit of cohesin preserves the genome integrity of embryonic stem cells김근필, 최의환, Seobin Yoon, Seo Jung Park생화학분자생물학회 · BMB Reports2023 · 제56권 제2호Origin of congenital coronary arterio-ventricular fistulae from anomalous epicardial and myocardial developmentBessiéres B., Conejo L., de la Pompa J. L., Gómez-Cabrero D., Guadix J. A., Houyel L., MacGrogan D., Meilhac S. M., Ortiz A., Palmquist-Gomes P., Pérez-Pomares J. M., Picazo B., Romero J. P., Ruiz-Villalba A.생화학분자생물학회 · Experimental and Molecular Medicine2023 · 제55권 Cohesin gene mutations in tumorigenesis: from discovery to clinical significance김정식, David A. Solomon, Todd Waldman생화학분자생물학회 · BMB Reports2014 · 제47권 제6호Cloning and characterization of the cardiac-specific Lrrc10 promoterJiajia Yuan, Jian Wang, Karen Ocorr, Qing Yang, Wuzhou Yuan, Xiao Yang, Xiaoyang Mo, Xiongwei Fan, Xiushan Wu, Yan Zhang, Yongqing Li, Yongqi Wan, Youliang Wang, Yuequn Wang, Yun Deng생화학분자생물학회 · BMB Reports2011 · 제44권 제2호

이 간행물의 다른 논문 (218건)

Big data and deep learning for RNA biologyJeon Hyeonseong, Baek Daehyun, Hwang Hyeonseo, Yeo Nagyeongpp. 1-29RGS19 activates the MYH9/β-catenin/c-Myc positive feedback loop in hepatocellular carcinomaXu Yanan, Ke Shanjia, Lu Shounan, Bai Miaoyu, Yu Hongjun, Yin Bing, Wang Chaoqun, Feng Zhigang, Li Zihao, Huang Jingjing, Li Xinglong, Qian Baolin, Hua Yongliang, Fu Yao, Sun Bei, Wu Yaohua, Ma Yongpp. 1-14Molecular mechanisms of circular RNA translationKim Yoon Ki, Hwang Hyun Jungpp. 1-9The m6A writer RBM15 drives the growth of triple-negative breast cancer cells through the stimulation of serine and glycine metabolismKim Ho, Yun Hye Jin, 이종호, Lee Su Bin, Kim Seok-Ho, Park Yun-Yong, Park Su Hwan, Ju Jin-Sung, Woo Hyunmin, Győrffy Balázs, Kim Eun-jeong, Han Hee Dong, Eyun Seong-ilpp. 1-15Neuron type-specific optogenetic stimulation for differential stroke recovery in chronic capsular infarctKim Ra Gyung, Cho Jongwook, Park Ji-Young, Kim Young Ro, Lee Min-Cheol, Kim Hyoung-Ihlpp. 1-11
원문 보기