Catalytic activity of Setd2 is essential for embryonic development in mice: establishment of a mouse model harboring patient-derived Setd2 mutation

Abstract

SETD2 is the only enzyme responsible for transcription-coupled histone H3 lysine 36 trimethylation (H3K36me3). Mutations in SETD2 cause human diseases including cancer and developmental defects. In mice, Setd2 is essential for embryonic vascular remodeling. Given that many epigenetic modifiers have recently been found to possess noncatalytic functions, it is unknown whether the major function(s) of Setd2 is dependent on its catalytic activity or not. Here, we established a site-specific knockin mouse model harboring a cancer patient-derived catalytically dead Setd2 (Setd2-CD). We found that the essentiality of Setd2 in mouse development is dependent on its methyltransferase activity, as the Setd2^CD/CD and Setd2^−/− mice showed similar embryonic lethal phenotypes and largely comparable gene expression patterns. However, compared with Setd2^−/−, the Setd2^CD/CD mice showed less severe defects in allantois development, and single-cell RNA-seq analysis revealed differentially regulated allantois-specific 5′ Hoxa cluster genes in these two models. Collectively, this study clarifies the importance of Setd2 catalytic activity in mouse development and provides a new model for comparative study of previously unrecognized Setd2 functions.

Keywords

Setd2 / H3K36 methylation / epigenetics / embryonic development / cancer

References

[1] Bird AP. CpG-rich islands and the function of DNA methylation. Nature 1986; 321(6067): 209–213

[2] Bestor TH, Verdine GL. DNA methyltransferases. Curr Opin Cell Biol 1994; 6(3): 380–389

[3] Jenuwein T, Allis CD. Translating the histone code. Science 2001; 293(5532): 1074–1080

[4] Aubert Y, Egolf S, Capell BC. The unexpected noncatalytic roles of histone modifiers in development and disease. Trends Genet 2019; 35(9): 645–657

[5] Morgan MAJ, Shilatifard A. Reevaluating the roles of histone-modifying enzymes and their associated chromatin modifications in transcriptional regulation. Nat Genet 2020; 52(12): 1271–1281

[6] Morgan MAJ, Shilatifard A. Epigenetic moonlighting: catalytic-independent functions of histone modifiers in regulating transcription. Sci Adv 2023; 9(16): eadg6593

[7] Strahl BD, Grant PA, Briggs SD, Sun ZW, Bone JR, Caldwell JA, Mollah S, Cook RG, Shabanowitz J, Hunt DF, Allis CD. Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. Mol Cell Biol 2002; 22(5): 1298–1306

[8] Sun XJ, Wei J, Wu XY, Hu M, Wang L, Wang HH, Zhang QH, Chen SJ, Huang QH, Chen Z. Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase. J Biol Chem 2005; 280(42): 35261–35271

[9] Kizer KO, Phatnani HP, Shibata Y, Hall H, Greenleaf AL, Strahl BD. A novel domain in Set2 mediates RNA polymerase II interaction and couples histone H3 K36 methylation with transcript elongation. Mol Cell Biol 2005; 25(8): 3305–3316

[10] Li M, Phatnani HP, Guan Z, Sage H, Greenleaf AL, Zhou P. Solution structure of the Set2-Rpb1 interacting domain of human Set2 and its interaction with the hyperphosphorylated C-terminal domain of Rpb1. Proc Natl Acad Sci USA 2005; 102(49): 17636–17641

[11] Vojnic E, Simon B, Strahl BD, Sattler M, Cramer P. Structure and carboxyl-terminal domain (CTD) binding of the Set2 SRI domain that couples histone H3 Lys36 methylation to transcription. J Biol Chem 2006; 281(1): 13–15

[12] Faber PW, Barnes GT, Srinidhi J, Chen J, Gusella JF, MacDonald ME. Huntingtin interacts with a family of WW domain proteins. Hum Mol Genet 1998; 7(9): 1463–1474

[13] Passani LA, Bedford MT, Faber PW, McGinnis KM, Sharp AH, Gusella JF, Vonsattel JP, MacDonald ME. Huntingtin’s WW domain partners in Huntington’s disease post-mortem brain fulfill genetic criteria for direct involvement in Huntington’s disease pathogenesis. Hum Mol Genet 2000; 9(14): 2175–2182

[14] Hesselberth JR, Miller JP, Golob A, Stajich JE, Michaud GA, Fields S. Comparative analysis of Saccharomyces cerevisiae WW domains and their interacting proteins. Genome Biol 2006; 7(4): R30

[15] Seervai RNH, Jangid RK, Karki M, Tripathi DN, Jung SY, Kearns SE, Verhey KJ, Cianfrocco MA, Millis BA, Tyska MJ, Mason FM, Rathmell WK, Park IY, Dere R, Walker CL. The Huntingtin-interacting protein SETD2/HYPB is an actin lysine methyltransferase. Sci Adv 2020; 6(40): eabb7854

[16] Yuan W, Xie J, Long C, Erdjument-Bromage H, Ding X, Zheng Y, Tempst P, Chen S, Zhu B, Reinberg D. Heterogeneous nuclear ribonucleoprotein L Is a subunit of human KMT3a/Set2 complex required for H3 Lys-36 trimethylation activity in vivo. J Biol Chem 2009; 284(23): 15701–15707

[17] Bhattacharya S, Levy MJ, Zhang N, Li H, Florens L, Washburn MP, Workman JL. The methyltransferase SETD2 couples transcription and splicing by engaging mRNA processing factors through its SHI domain. Nat Commun 2021; 12(1): 1443

[18] Bhattacharya S, Wang S, Reddy D, Shen S, Zhang Y, Zhang N, Li H, Washburn MP, Florens L, Shi Y, Workman JL, Li F. Structural basis of the interaction between SETD2 methyltransferase and hnRNP L paralogs for governing co-transcriptional splicing. Nat Commun 2021; 12(1): 6452

[19] Bhattacharya S, Lange JJ, Levy M, Florens L, Washburn MP, Workman JL. The disordered regions of the methyltransferase SETD2 govern its function by regulating its proteolysis and phase separation. J Biol Chem 2021; 297(3): 101075

[20] Li J, Moazed D, Gygi SP. Association of the histone methyltransferase Set2 with RNA polymerase II plays a role in transcription elongation. J Biol Chem 2002; 277(51): 49383–49388

[21] Krogan NJ, Kim M, Tong A, Golshani A, Cagney G, Canadien V, Richards DP, Beattie BK, Emili A, Boone C, Shilatifard A, Buratowski S, Greenblatt J. Methylation of histone H3 by Set2 in Saccharomyces cerevisiae is linked to transcriptional elongation by RNA polymerase II. Mol Cell Biol 2003; 23(12): 4207–4218

[22] Li B, Howe L, Anderson S, Yates JR 3rd, Workman JL. The Set2 histone methyltransferase functions through the phosphorylated carboxyl-terminal domain of RNA polymerase II. J Biol Chem 2003; 278(11): 8897–8903

[23] Xiao T, Hall H, Kizer KO, Shibata Y, Hall MC, Borchers CH, Strahl BD. Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast. Genes Dev 2003; 17(5): 654–663

[24] Schaft D, Roguev A, Kotovic KM, Shevchenko A, Sarov M, Shevchenko A, Neugebauer KM, Stewart AF. The histone 3 lysine 36 methyltransferase, SET2, is involved in transcriptional elongation. Nucleic Acids Res 2003; 31(10): 2475–2482

[25] Edmunds JW, Mahadevan LC, Clayton AL. Dynamic histone H3 methylation during gene induction: HYPB/Setd2 mediates all H3K36 trimethylation. EMBO J 2008; 27(2): 406–420

[26] Sun XJ, Xu PF, Zhou T, Hu M, Fu CT, Zhang Y, Jin Y, Chen Y, Chen SJ, Huang QH, Liu TX, Chen Z. Genome-wide survey and developmental expression mapping of zebrafish SET domain-containing genes. PLoS One 2008; 3(1): e1499

[27] Hu M, Sun XJ, Zhang YL, Kuang Y, Hu CQ, Wu WL, Shen SH, Du TT, Li H, He F, Xiao HS, Wang ZG, Liu TX, Lu H, Huang QH, Chen SJ, Chen Z. Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. Proc Natl Acad Sci USA 2010; 107(7): 2956–2961

[28] Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell 2007; 129(4): 823–837

[29] Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin ML, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T, Mulderrig L, Mudie L, O’Meara S, Pleasance E, Rajasingham A, Shepherd R, Smith R, Stebbings L, Stephens P, Tang G, Tarpey PS, Turrell K, Dykema KJ, Khoo SK, Petillo D, Wondergem B, Anema J, Kahnoski RJ, Teh BT, Stratton MR, Futreal PA. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 2010; 463(7279): 360–363

[30] Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MDM, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L. Mutational landscape and significance across 12 major cancer types. Nature 2013; 502(7471): 333–339

[31] Luscan A, Laurendeau I, Malan V, Francannet C, Odent S, Giuliano F, Lacombe D, Touraine R, Vidaud M, Pasmant E, Cormier-Daire V. Mutations in SETD2 cause a novel overgrowth condition. J Med Genet 2014; 51(8): 512–517

[32] D’Gama AM, Pochareddy S, Li M, Jamuar SS, Reiff RE, Lam AN, Sestan N, Walsh CA. Targeted DNA sequencing from autism spectrum disorder brains implicates multiple genetic mechanisms. Neuron 2015; 88(5): 910–917

[33] Liu DJ, Zhang F, Chen Y, Jin Y, Zhang YL, Chen SB, Xie YY, Huang QH, Zhao WL, Wang L, Xu PF, Chen Z, Chen SJ, Li B, Zhang A, Sun XJ. setd2 knockout zebrafish is viable and fertile: differential and developmental stress-related requirements for Setd2 and histone H3K36 trimethylation in different vertebrate animals. Cell Discov 2020; 6(1): 72

[34] Park IY, Powell RT, Tripathi DN, Dere R, Ho TH, Blasius TL, Chiang YC, Davis IJ, Fahey CC, Hacker KE, Verhey KJ, Bedford MT, Jonasch E, Rathmell WK, Walker CL. Dual chromatin and cytoskeletal remodeling by SETD2. Cell 2016; 166(4): 950–962

[35] Chen K, Liu J, Liu S, Xia M, Zhang X, Han D, Jiang Y, Wang C, Cao X. Methyltransferase SETD2-mediated methylation of STAT1 is critical for interferon antiviral activity. Cell 2017; 170(3): 492–506.e14

[36] Mar BG, Chu SH, Kahn JD, Krivtsov AV, Koche R, Castellano CA, Kotlier JL, Zon RL, McConkey ME, Chabon J, Chappell R, Grauman PV, Hsieh JJ, Armstrong SA, Ebert BL. SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia. Blood 2017; 130(24): 2631–2641

[37] Moffitt AB, Ondrejka SL, McKinney M, Rempel RE, Goodlad JR, Teh CH, Leppa S, Mannisto S, Kovanen PE, Tse E, Au-Yeung RKH, Kwong YL, Srivastava G, Iqbal J, Yu J, Naresh K, Villa D, Gascoyne RD, Said J, Czader MB, Chadburn A, Richards KL, Rajagopalan D, Davis NS, Smith EC, Palus BC, Tzeng TJ, Healy JA, Lugar PL, Datta J, Love C, Levy S, Dunson DB, Zhuang Y, Hsi ED, Dave SS. Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2. J Exp Med 2017; 214(5): 1371–1386

[38] Zhang YL, Sun JW, Xie YY, Zhou Y, Liu P, Song JC, Xu CH, Wang L, Liu D, Xu AN, Chen Z, Chen SJ, Sun XJ, Huang QH. Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. Cell Res 2018; 28(4): 476–490

[39] Zhou Y, Yan X, Feng X, Bu J, Dong Y, Lin P, Hayashi Y, Huang R, Olsson A, Andreassen PR, Grimes HL, Wang QF, Cheng T, Xiao Z, Jin J, Huang G. Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation. Haematologica 2018; 103(7): 1110–1123

[40] Zuo X, Rong B, Li L, Lv R, Lan F, Tong MH. The histone methyltransferase SETD2 is required for expression of acrosin-binding protein 1 and protamines and essential for spermiogenesis in mice. J Biol Chem 2018; 293(24): 9188–9197

[41] Xu L, Zheng Y, Li X, Wang A, Huo D, Li Q, Wang S, Luo Z, Liu Y, Xu F, Wu X, Wu M, Zhou Y. Abnormal neocortex arealization and Sotos-like syndrome-associated behavior in Setd2 mutant mice. Sci Adv 2021; 7(1): eaba1180

[42] Xie Y, Sahin M, Wakamatsu T, Inoue-Yamauchi A, Zhao W, Han S, Nargund AM, Yang S, Lyu Y, Hsieh JJ, Leslie CS, Cheng EH. SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis. JCI Insight 2023; 8(4): e154120

[43] Yuan H, Li N, Fu D, Ren J, Hui J, Peng J, Liu Y, Qiu T, Jiang M, Pan Q, Han Y, Wang X, Li Q, Qin J. Histone methyltransferase SETD2 modulates alternative splicing to inhibit intestinal tumorigenesis. J Clin Invest 2017; 127(9): 3375–3391

[44] Chen BY, Song J, Hu CL, Chen SB, Zhang Q, Xu CH, Wu JC, Hou D, Sun M, Zhang YL, Liu N, Yu PC, Liu P, Zong LJ, Zhang JY, Dai RF, Lan F, Huang QH, Zhang SJ, Nimer SD, Chen Z, Chen SJ, Sun XJ, Wang L. SETD2 deficiency accelerates MDS-associated leukemogenesis via S100a9 in NHD13 mice and predicts poor prognosis in MDS. Blood 2020; 135(25): 2271–2285

[45] Niu N, Lu P, Yang Y, He R, Zhang L, Shi J, Wu J, Yang M, Zhang ZG, Wang LW, Gao WQ, Habtezion A, Xiao GG, Sun Y, Li L, Xue J. Loss of Setd2 promotes Kras-induced acinar-to-ductal metaplasia and epithelia-mesenchymal transition during pancreatic carcinogenesis. Gut 2020; 69(4): 715–726

[46] Yuan H, Han Y, Wang X, Li N, Liu Q, Yin Y, Wang H, Pan L, Li L, Song K, Qiu T, Pan Q, Chen Q, Zhang G, Zang Y, Tan M, Zhang J, Li Q, Wang X, Jiang J, Qin J. SETD2 restricts prostate cancer metastasis by integrating EZH2 and AMPK signaling pathways. Cancer Cell 2020; 38(3): 350–365.e7

[47] Rao H, Li X, Liu M, Liu J, Feng W, Tang H, Xu J, Gao WQ, Li L. Multilevel regulation of beta-catenin activity by SETD2 suppresses the transition from polycystic kidney disease to clear cell renal cell carcinoma. Cancer Res 2021; 81(13): 3554–3567

[48] Rao H, Liu C, Wang A, Ma C, Xu Y, Ye T, Su W, Zhou P, Gao WQ, Li L, Ding X. SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer. Nat Commun 2023; 14(1): 7572

[49] Song J, Du L, Liu P, Wang F, Zhang B, Xie Y, Lu J, Jin Y, Zhou Y, Lv G, Zhang J, Chen S, Chen Z, Sun X, Zhang Y, Huang Q. Intra-heterogeneity in transcription and chemoresistant property of leukemia-initiating cells in murine Setd2^−/− acute myeloid leukemia. Cancer Commun (Lond) 2021; 41(9): 867–888

[50] Ma C, Liu M, Feng W, Rao H, Zhang W, Liu C, Xu Y, Wang Z, Teng Y, Yang X, Ni L, Xu J, Gao WQ, Lu B, Li L. Loss of SETD2 aggravates colorectal cancer progression caused by SMAD4 deletion through the RAS/ERK signalling pathway. Clin Transl Med 2023; 13(11): e1475

[51] Zheng X, Luo Y, Xiong Y, Liu X, Zeng C, Lu X, Wang X, Cheng Y, Wang S, Lan H, Wang K, Weng Z, Bi W, Gan X, Jia X, Wang L, Wang Y. Tumor cell-intrinsic SETD2 inactivation sensitizes cancer cells to immune checkpoint blockade through the NR2F1-STAT1 pathway. J Immunother Cancer 2023; 11(12): e007678

[52] Sun XJ, Wang Z, Wang L, Jiang Y, Kost N, Soong TD, Chen WY, Tang Z, Nakadai T, Elemento O, Fischle W, Melnick A, Patel DJ, Nimer SD, Roeder RG. A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis. Nature 2013; 500(7460): 93–97

[53] Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods 2008; 5(7): 621–628

[54] Zhang F, Zeng QY, Xu H, Xu AN, Liu DJ, Li NZ, Chen Y, Jin Y, Xu CH, Feng CZ, Zhang YL, Liu D, Liu N, Xie YY, Yu SH, Yuan H, Xue K, Shi JY, Liu TX, Xu PF, Zhao WL, Zhou Y, Wang L, Huang QH, Chen Z, Chen SJ, Zhou XL, Sun XJ. Selective and competitive functions of the AAR and UPR pathways in stress-induced angiogenesis. Cell Discov 2021; 7(1): 98

[55] Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102(43): 15545–15550

[56] Grosswendt S, Kretzmer H, Smith ZD, Kumar AS, Hetzel S, Wittler L, Klages S, Timmermann B, Mukherji S, Meissner A. Epigenetic regulator function through mouse gastrulation. Nature 2020; 584(7819): 102–108

[57] Fahey CC, Davis IJ. SETting the stage for cancer development: SETD2 and the consequences of lost methylation. Cold Spring Harb Perspect Med 2017; 7(5): a026468

[58] Patnaik MM, Abdel-Wahab O. SETD2—linking stem cell survival and transformation. Cell Res 2018; 28(4): 393–394

[59] Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012; 366(10): 883–892

[60] The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013; 499(7456): 43–49

[61] Kanu N, Gronroos E, Martinez P, Burrell RA, Yi Goh X, Bartkova J, Maya-Mendoza A, Mistrik M, Rowan AJ, Patel H, Rabinowitz A, East P, Wilson G, Santos CR, McGranahan N, Gulati S, Gerlinger M, Birkbak NJ, Joshi T, Alexandrov LB, Stratton MR, Powles T, Matthews N, Bates PA, Stewart A, Szallasi Z, Larkin J, Bartek J, Swanton C. SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene 2015; 34(46): 5699–5708

[62] González-Rodríguez P, Engskog-Vlachos P, Zhang H, Murgoci AN, Zerdes I, Joseph B. SETD2 mutation in renal clear cell carcinoma suppress autophagy via regulation of ATG12. Cell Death Dis 2020; 11(1): 69

[63] Xie Y, Sahin M, Sinha S, Wang Y, Nargund AM, Lyu Y, Han S, Dong Y, Hsieh JJ, Leslie CS, Cheng EH. SETD2 loss perturbs the kidney cancer epigenetic landscape to promote metastasis and engenders actionable dependencies on histone chaperone complexes. Nat Cancer 2022; 3(2): 188–202

[64] Liu XD, Zhang YT, McGrail DJ, Zhang X, Lam T, Hoang A, Hasanov E, Manyam G, Peterson CB, Zhu H, Kumar SV, Akbani R, Pilie PG, Tannir NM, Peng G, Jonasch E. SETD2 loss and ATR inhibition synergize to promote cGAS signaling and immunotherapy response in renal cell carcinoma. Clin Cancer Res 2023; 29(19): 4002–4015

[65] Yang S, Zheng X, Lu C, Li GM, Allis CD, Li H. Molecular basis for oncohistone H3 recognition by SETD2 methyltransferase. Genes Dev 2016; 30(14): 1611–1616

[66] Liu Y, Zhang Y, Xue H, Cao M, Bai G, Mu Z, Yao Y, Sun S, Fang D, Huang J. Cryo-EM structure of SETD2/Set2 methyltransferase bound to a nucleosome containing oncohistone mutations. Cell Discov 2021; 7(1): 32

[67] Zhu K, Lei PJ, Ju LG, Wang X, Huang K, Yang B, Shao C, Zhu Y, Wei G, Fu XD, Li L, Wu M. SPOP-containing complex regulates SETD2 stability and H3K36me3-coupled alternative splicing. Nucleic Acids Res 2017; 45(1): 92–105

[68] Bhattacharya S, Lange JJ, Levy M, Florens L, Washburn MP, Workman JL. The disordered regions of the methyltransferase SETD2 govern its function by regulating its proteolysis and phase separation. J Biol Chem 2021; 297(3): 101075

[69] Gallardo T, Shirley L, John GB, Castrillon DH. Generation of a germ cell-specific mouse transgenic Cre line, Vasa-Cre. Genesis 2007; 45(6): 413–417

[70] Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 2015; 1(6): 417–425

[71] Gene Ontology Consortium; Aleksander SA, Balhoff J, Carbon S, Cherry JM, Drabkin HJ, Ebert D, Feuermann M, Gaudet P, Harris NL, Hill DP, Lee R, Mi H, Moxon S, Mungall CJ, Muruganugan A, Mushayahama T, Sternberg PW, Thomas PD, Van Auken K, Ramsey J, Siegele DA, Chisholm RL, Fey P, Aspromonte MC, Nugnes MV, Quaglia F, Tosatto S, Giglio M, Nadendla S, Antonazzo G, Attrill H, Dos Santos G, Marygold S, Strelets V, Tabone CJ, Thurmond J, Zhou P, Ahmed SH, Asanitthong P, Luna Buitrago D, Erdol MN, Gage MC, Ali Kadhum M, Li KYC, Long M, Michalak A, Pesala A, Pritazahra A, Saverimuttu SCC, Su R, Thurlow KE, Lovering RC, Logie C, Oliferenko S, Blake J, Christie K, Corbani L, Dolan ME, Drabkin HJ, Hill DP, Ni L, Sitnikov D, Smith C, Cuzick A, Seager J, Cooper L, Elser J, Jaiswal P, Gupta P, Jaiswal P, Naithani S, Lera-Ramirez M, Rutherford K, Wood V, De Pons JL, Dwinell MR, Hayman GT, Kaldunski ML, Kwitek AE, Laulederkind SJF, Tutaj MA, Vedi M, Wang SJ, D'Eustachio P, Aimo L, Axelsen K, Bridge A, Hyka-Nouspikel N, Morgat A, Aleksander SA, Cherry JM, Engel SR, Karra K, Miyasato SR, Nash RS, Skrzypek MS, Weng S, Wong ED, Bakker E, Berardini TZ, Reiser L, Auchincloss A, Axelsen K, Argoud-Puy G, Blatter MC, Boutet E, Breuza L, Bridge A, Casals-Casas C, Coudert E, Estreicher A, Livia Famiglietti M, Feuermann M, Gos A, Gruaz-Gumowski N, Hulo C, Hyka-Nouspikel N, Jungo F, Le Mercier P, Lieberherr D, Masson P, Morgat A, Pedruzzi I, Pourcel L, Poux S, Rivoire C, Sundaram S, Bateman A, Bowler-Barnett E, Bye-A-Jee H, Denny P, Ignatchenko A, Ishtiaq R, Lock A, Lussi Y, Magrane M, Martin MJ, Orchard S, Raposo P, Speretta E, Tyagi N, Warner K, Zaru R, Diehl AD, Lee R, Chan J, Diamantakis S, Raciti D, Zarowiecki M, Fisher M, James-Zorn C, Ponferrada V, Zorn A, Ramachandran S, Ruzicka L, Westerfield M. The Gene Ontology knowledgebase in 2023. Genetics 2023; 224(1): iyad031

[72] Myllyharju J, Kivirikko KI. Collagens and collagen-related diseases. Ann Med 2001; 33(1): 7–21

[73] ChuML. Structural Proteins: Genes for Collagen. Encyclopedia of Life Sciences. 2011

[74] Shaut CA, Keene DR, Sorensen LK, Li DY, Stadler HS. HOXA13 is essential for placental vascular patterning and labyrinth endothelial specification. PLoS Genet 2008; 4(5): e1000073

[75] Scotti M, Kmita M. Recruitment of 5′ Hoxa genes in the allantois is essential for proper extra-embryonic function in placental mammals. Development 2012; 139(4): 731–739

[76] Dorighi KM, Swigut T, Henriques T, Bhanu NV, Scruggs BS, Nady N, Still CD 2nd, Garcia BA, Adelman K, Wysocka J. Mll3 and Mll4 facilitate enhancer RNA synthesis and transcription from promoters independently of H3K4 monomethylation. Mol Cell 2017; 66(4): 568–576.e4

[77] Rickels R, Herz HM, Sze CC, Cao K, Morgan MA, Collings CK, Gause M, Takahashi YH, Wang L, Rendleman EJ, Marshall SA, Krueger A, Bartom ET, Piunti A, Smith ER, Abshiru NA, Kelleher NL, Dorsett D, Shilatifard A. Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability. Nat Genet 2017; 49(11): 1647–1653

[78] Rickels R, Wang L, Iwanaszko M, Ozark PA, Morgan MA, Piunti A, Khalatyan N, Soliman SHA, Rendleman EJ, Savas JN, Smith ER, Shilatifard A. A small UTX stabilization domain of Trr is conserved within mammalian MLL3–4/COMPASS and is sufficient to rescue loss of viability in null animals. Genes Dev 2020; 34(21–22): 1493–1502

[79] Ciabrelli F, Rabbani L, Cardamone F, Zenk F, Loser E, Schachtle MA, Mazina M, Loubiere V, Iovino N. CBP and Gcn5 drive zygotic genome activation independently of their catalytic activity. Sci Adv 2023; 9(16): eadf2687

[80] Takebayashi S, Tamura T, Matsuoka C, Okano M. Major and essential role for the DNA methylation mark in mouse embryogenesis and stable association of DNMT1 with newly replicated regions. Mol Cell Biol 2007; 27(23): 8243–8258

[81] McDaniel SL, Strahl BD. Shaping the cellular landscape with Set2/SETD2 methylation. Cell Mol Life Sci 2017; 74(18): 3317–3334

[82] Li J, Ahn JH, Wang GG. Understanding histone H3 lysine 36 methylation and its deregulation in disease. Cell Mol Life Sci 2019; 76(15): 2899–2916

[83] Li B, Gogol M, Carey M, Pattenden SG, Seidel C, Workman JL. Infrequently transcribed long genes depend on the Set2/Rpd3S pathway for accurate transcription. Genes Dev 2007; 21(11): 1422–1430

[84] Lickwar CR, Rao B, Shabalin AA, Nobel AB, Strahl BD, Lieb JD. The Set2/Rpd3S pathway suppresses cryptic transcription without regard to gene length or transcription frequency. PLoS One 2009; 4(3): e4886

[85] Finogenova K, Bonnet J, Poepsel S, Schafer IB, Finkl K, Schmid K, Litz C, Strauss M, Benda C, Muller J. Structural basis for PRC2 decoding of active histone methylation marks H3K36me2/3. eLife 2020; 9: e61964

[86] Kim JH, Lee BB, Oh YM, Zhu C, Steinmetz LM, Lee Y, Kim WK, Lee SB, Buratowski S, Kim T. Modulation of mRNA and lncRNA expression dynamics by the Set2-Rpd3S pathway. Nat Commun 2016; 7(1): 13534

[87] Venkatesh S, Li H, Gogol MM, Workman JL. Selective suppression of antisense transcription by Set2-mediated H3K36 methylation. Nat Commun 2016; 7(1): 13610

[88] Adelman JP, Bond CT, Douglass J, Herbert E. Two mammalian genes transcribed from opposite strands of the same DNA locus. Science 1987; 235(4795): 1514–1517

[89] Rosikiewicz W, Suzuki Y, Makalowska I. OverGeneDB: a database of 5′ end protein coding overlapping genes in human and mouse genomes. Nucleic Acids Res 2018; 46(D1): D186–D193

[90] Liu D, Xu C, Liu Y, Ouyang W, Lin S, Xu A, Zhang Y, Xie Y, Huang Q, Zhao W, Chen Z, Wang L, Chen S, Huang J, Wu ZB, Sun X. A systematic survey of LU domain-containing proteins reveals a novel human gene, LY6A, which encodes the candidate ortholog of mouse Ly-6A/Sca-1 and is aberrantly expressed in pituitary tumors. Front Med 2023; 17(3): 458–475

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