Abstract
Recent technological advancements and genome-wide studies provide compelling evidence that dynamic chromatin interaction and three-dimensional genome organization in nuclei play an important role in regulating gene expression. Mammalian genomes consist of many small functional domains termed topologically associated domains (TADs), many of them organized by CCCTC-binding factor (CTCF) and the cohesion complex. Changes in genome TADs might result in inappropriate promoter/enhancer communications leading to activation of oncogenes or suppression of tumor suppressors. During normal hematopoiesis and leukemogenesis, genome structure alters considerably to facilitate normal and malignant hematopoiesis, respectively. Delineating theses normal and abnormal processes will evolve our understanding of disease pathogenesis and development of potential treatment strategies. This review highlights the role of CTCF and its associated protein complexes in three-dimensional genome organization in development and leukemogenesis, as well as the roles of CTCF boundary defined TAD in transcription regulation. We further explore the function of chromatin modulators, such as CTCF, cohesin, and long noncoding RNAs (lncRNAs) in chromosomal interactions and hematopoietic genome organization. Finally, we focus on the implication of 3D genome alteration in the pathogenesis of leukemia and provide a scientific basis for targeted intervention.
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References
Valton AL, Dekker J. TAD disruption as oncogenic driver. Curr Opin Genet Dev. 2016;36:34–40.
Groschel S, Sanders MA, Hoogenboezem R, de Wit E, Bouwman BAM, Erpelinck C, et al. A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia. Cell. 2014;157:369–81.
Taberlay PC, Achinger-Kawecka J, Lun AT, Buske FA, Sabir K, Gould CM, et al. Three-dimensional disorganization of the cancer genome occurs coincident with long-range genetic and epigenetic alterations. Genome Res. 2016;26:719–31.
Luo H, Wang F, Zha J, Li H, Yan B, Du Q, et al. CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia. Blood. 2018;132:837–48.
Narendra V, Rocha PP, An D, Raviram R, Skok JA, Mazzoni EO, et al. CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation. Science. 2015;347:1017–21.
Cremer T, Cremer C, Schneider T, Baumann H, Hens L, Kirsch-Volders M. Analysis of chromosome positions in the interphase nucleus of Chinese hamster cells by laser-UV-microirradiation experiments. Hum Genet. 1982;62:201–9.
Cremer T, Cremer M, Dietzel S, Muller S, Solovei I, Fakan S. Chromosome territories-a functional nuclear landscape. Curr Opin Cell Biol. 2006;18:307–16.
Noordermeer D, Branco MR, Splinter E, Klous P, van Ijcken W, Swagemakers S, et al. Transcription and chromatin organization of a housekeeping gene cluster containing an integrated beta-globin locus control region. PLoS Genet. 2008;4:e1000016.
Phillips JE, Corces VG. CTCF: master weaver of the genome. Cell. 2009;137:1194–211.
Rowley MJ, Corces VG. Organizational principles of 3D genome architecture. Nat Rev Genet. 2018;19:789–800.
Dowen JM, Fan ZP, Hnisz D, Ren G, Abraham BJ, Zhang LN, et al. Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes. Cell. 2014;159:374–87.
Tang Z, Luo OJ, Li X, Zheng M, Zhu JJ, Szalaj P, et al. CTCF-mediated human 3D genome architecture reveals chromatin topology for transcription. Cell. 2015;163:1611–27.
Bell AC, West AG, Felsenfeld G. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell. 1999;98:387–96.
Chung JH, Whiteley M, Felsenfeld G. A 5’ element of the chicken beta-globin domain serves as an insulator in human erythroid cells and protects against position effect in Drosophila. Cell. 1993;74:505–14.
Bushey AM, Dorman ER, Corces VG. Chromatin insulators: regulatory mechanisms and epigenetic inheritance. Mol Cell. 2008;32:1–9.
Gaszner M, Felsenfeld G. Insulators: exploiting transcriptional and epigenetic mechanisms. Nat Rev Genet. 2006;7:703–13.
West AG, Gaszner M, Felsenfeld G. Insulators: many functions, many mechanisms. Genes Dev. 2002;16:271–88.
Cuddapah S, Jothi R, Schones DE, Roh TY, Cui K, Zhao K. Global analysis of the insulator binding protein CTCF in chromatin barrier regions reveals demarcation of active and repressive domains. Genome Res. 2009;19:24–32.
Zlatanova J, Caiafa P. CTCF and its protein partners: divide and rule? J Cell Sci. 2009;122:1275–84.
Yusufzai TM, Tagami H, Nakatani Y, Felsenfeld G. CTCF tethers an insulator to subnuclear sites, suggesting shared insulator mechanisms across species. Mol Cell. 2004;13:291–8.
Dekker J, Mirny L. The 3D genome as moderator of chromosomal communication. Cell. 2016;164:1110–21.
Li Y, Haarhuis JHI, Sedeno Cacciatore A, Oldenkamp R, van Ruiten MS, Willems L, et al. The structural basis for cohesin-CTCF-anchored loops. Nature. 2020;578:472–6.
Parelho V, Hadjur S, Spivakov M, Leleu M, Sauer S, Gregson HC, et al. Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell. 2008;132:422–33.
Wendt KS, Yoshida K, Itoh T, Bando M, Koch B, Schirghuber E, et al. Cohesin mediates transcriptional insulation by CCCTC-binding factor. Nature. 2008;451:796–801.
Rubio ED, Reiss DJ, Welcsh PL, Disteche CM, Filippova GN, Baliga NS, et al. CTCF physically links cohesin to chromatin. Proc Natl Acad Sci USA. 2008;105:8309–14.
Fudenberg G, Imakaev M, Lu C, Goloborodko A, Abdennur N, Mirny LA. Formation of chromosomal domains by loop extrusion. Cell Rep. 2016;15:2038–49.
Nuebler J, Fudenberg G, Imakaev M, Abdennur N, Mirny LA. Chromatin organization by an interplay of loop extrusion and compartmental segregation. Proc Natl Acad Sci USA. 2018;115:E6697–706.
Zuin J, Dixon JR, van der Reijden MI, Ye Z, Kolovos P, Brouwer RW, et al. Cohesin and CTCF differentially affect chromatin architecture and gene expression in human cells. Proc Natl Acad Sci USA. 2014;111:996–1001.
Hadjur S, Williams LM, Ryan NK, Cobb BS, Sexton T, Fraser P, et al. Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus. Nature. 2009;460:410–3.
Nativio R, Wendt KS, Ito Y, Huddleston JE, Uribe-Lewis S, Woodfine K, et al. Cohesin is required for higher-order chromatin conformation at the imprinted IGF2-H19 locus. PLoS Genet. 2009;5:e1000739.
Kojic A, Cuadrado A, De Koninck M, Gimenez-Llorente D, Rodriguez-Corsino M, Gomez-Lopez G, et al. Distinct roles of cohesin-SA1 and cohesin-SA2 in 3D chromosome organization. Nat Struct Mol Biol. 2018;25:496–504.
Phillips-Cremins JE, Sauria ME, Sanyal A, Gerasimova TI, Lajoie BR, Bell JS, et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell. 2013;153:1281–95.
Yan J, Enge M, Whitington T, Dave K, Liu J, Sur I, et al. Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites. Cell. 2013;154:801–13.
Yao H, Brick K, Evrard Y, Xiao T, Camerini-Otero RD, Felsenfeld G. Mediation of CTCF transcriptional insulation by DEAD-box RNA-binding protein p68 and steroid receptor RNA activator SRA. Genes Dev. 2010;24:2543–55.
Kung JT, Kesner B, An JY, Ahn JY, Cifuentes-Rojas C, Colognori D, et al. Locus-specific targeting to the X chromosome revealed by the RNA interactome of CTCF. Mol Cell. 2015;57:361–75.
Lee JT, Bartolomei MS. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell. 2013;152:1308–23.
Saldana-Meyer R, Rodriguez-Hernaez J, Escobar T, Nishana M, Jacome-Lopez K, Nora EP, et al. RNA interactions are essential for CTCF-mediated genome organization. Mol Cell. 2019;76:412–22.e415
Hansen AS, Hsieh TS, Cattoglio C, Pustova I, Saldana-Meyer R, Reinberg D, et al. Distinct classes of chromatin loops revealed by deletion of an RNA-binding region in CTCF. Mol Cell. 2019;76:395–411.e313.
Luo H, Zhu G, Xu J, Lai Q, Yan B, Guo Y, et al. HOTTIP lncRNA promotes hematopoietic stem cell self-renewal leading to AML-like disease in mice. Cancer Cell. 2019;36:645–59.e648.
Wang KC, Yang YW, Liu B, Sanyal A, Corces-Zimmerman R, Chen Y, et al. A long noncoding RNA maintains active chromatin to coordinate homeotic gene expression. Nature. 2011;472:120–4.
Drabkin HA, Parsy C, Ferguson K, Guilhot F, Lacotte L, Roy L, et al. Quantitative HOX expression in chromosomally defined subsets of acute myelogenous leukemia. Leukemia. 2002;16:186–95.
Andreeff M, Ruvolo V, Gadgil S, Zeng C, Coombes K, Chen W, et al. HOX expression patterns identify a common signature for favorable AML. Leukemia. 2008;22:2041–7.
Dou DR, Calvanese V, Sierra MI, Nguyen AT, Minasian A, Saarikoski P, et al. Medial HOXA genes demarcate haematopoietic stem cell fate during human development. Nat Cell Biol. 2016;18:595–606.
Lawrence HJ, Christensen J, Fong S, Hu YL, Weissman I, Sauvageau G, et al. Loss of expression of the Hoxa-9 homeobox gene impairs the proliferation and repopulating ability of hematopoietic stem cells. Blood. 2005;106:3988–94.
Deng C, Li Y, Liang S, Cui K, Salz T, Yang H, et al. USF1 and hSET1A mediated epigenetic modifications regulate lineage differentiation and HoxB4 transcription. PLoS Genet. 2013;9:e1003524.
Alharbi RA, Pettengell R, Pandha HS, Morgan R. The role of HOX genes in normal hematopoiesis and acute leukemia. Leukemia. 2013;27:1000–8.
Spencer DH, Young MA, Lamprecht TL, Helton NM, Fulton R, O’Laughlin M, et al. Epigenomic analysis of the HOX gene loci reveals mechanisms that may control canonical expression patterns in AML and normal hematopoietic cells. Leukemia. 2015;29:1279–89.
Dixon JR, Selvaraj S, Yue F, Kim A, Li Y, Shen Y, et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature. 2012;485:376–80.
Handoko L, Xu H, Li G, Ngan CY, Chew E, Schnapp M, et al. CTCF-mediated functional chromatin interactome in pluripotent cells. Nat Genet. 2011;43:630–8.
Zhao Z, Tavoosidana G, Sjolinder M, Gondor A, Mariano P, Wang S, et al. Circular chromosome conformation capture (4C) uncovers extensive networks of epigenetically regulated intra- and interchromosomal interactions. Nat Genet. 2006;38:1341–7.
Wallace JA, Felsenfeld G. We gather together: insulators and genome organization. Curr Opin Genet Dev. 2007;17:400–7.
Nora EP, Lajoie BR, Schulz EG, Giorgetti L, Okamoto I, Servant N, et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature. 2012;485:381–5.
Sexton T, Kurukuti S, Mitchell JA, Umlauf D, Nagano T, Fraser P. Sensitive detection of chromatin coassociations using enhanced chromosome conformation capture on chip. Nat Protoc. 2012;7:1335–50.
Ren G, Jin W, Cui K, Rodrigez J, Hu G, Zhang Z, et al. CTCF-mediated enhancer-promoter interaction is a critical regulator of cell-to-cell variation of gene expression. Mol Cell. 2017;67:1049–58.e1046.
Viny AD, Bowman RL, Liu Y, Lavallee VP, Eisman SE, Xiao W, et al. Cohesin members Stag1 and Stag2 display distinct roles in chromatin accessibility and topological control of HSC self-renewal and differentiation. Cell Stem Cell. 2019;25:682–96.e688.
Rodriguez-Carballo E, Lopez-Delisle L, Zhan Y, Fabre PJ, Beccari L, El-Idrissi I, et al. The HoxD cluster is a dynamic and resilient TAD boundary controlling the segregation of antagonistic regulatory landscapes. Genes Dev. 2017;31:2264–81.
Narendra V, Bulajic M, Dekker J, Mazzoni EO, Reinberg D. CTCF-mediated topological boundaries during development foster appropriate gene regulation. Genes Dev. 2016;30:2657–62.
Guo Y, Xu Q, Canzio D, Shou J, Li J, Gorkin DU, et al. CRISPR inversion of CTCF sites alters genome topology and enhancer/promoter function. Cell. 2015;162:900–10.
de Wit E, Vos ES, Holwerda SJ, Valdes-Quezada C, Verstegen MJ, Teunissen H, et al. CTCF binding polarity determines chromatin looping. Mol Cell. 2015;60:676–84.
Schoenfelder S, Fraser P. Long-range enhancer-promoter contacts in gene expression control. Nat Rev Genet. 2019;20:437–55.
Zhang Y, Wong CH, Birnbaum RY, Li G, Favaro R, Ngan CY, et al. Chromatin connectivity maps reveal dynamic promoter-enhancer long-range associations. Nature. 2013;504:306–10.
Sanyal A, Lajoie BR, Jain G, Dekker J. The long-range interaction landscape of gene promoters. Nature. 2012;489:109–13.
Zhang H, Emerson DJ, Gilgenast TG, Titus KR, Lan Y, Huang P, et al. Chromatin structure dynamics during the mitosis-to-G1 phase transition. Nature. 2019;576:158–62.
Misteli T. Beyond the sequence: cellular organization of genome function. Cell. 2007;128:787–800.
Grimwade D, Ivey A, Huntly BJ. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood. 2016;127:29–41.
Patel JP, Gonen M, Figueroa ME, Fernandez H, Sun Z, Racevskis J, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366:1079–89.
Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.
Haas S, Trumpp A, Milsom MD. Causes and consequences of hematopoietic stem cell heterogeneity. Cell Stem Cell. 2018;22:627–38.
Chen C, Yu W, Tober J, Gao P, He B, Lee K, et al. Spatial genome re-organization between fetal and adult hematopoietic stem cells. Cell Rep. 2019;29:4200–11.e4207.
Patel B, Kang Y, Cui K, Litt M, Riberio MS, Deng C, et al. Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia. Leukemia. 2014;28:349–61.
Zhou Y, Kurukuti S, Saffrey P, Vukovic M, Michie AM, Strogantsev R, et al. Chromatin looping defines expression of TAL1, its flanking genes, and regulation in T-ALL. Blood. 2013;122:4199–209.
Li Y, Liao Z, Luo H, Benyoucef A, Kang Y, Lai Q, et al. Alteration of CTCF-associated chromatin neighborhood inhibits TAL1-driven oncogenic transcription program and leukemogenesis. Nucleic Acids Res. 2020;48:3119–33.
Hyle J, Zhang Y, Wright S, Xu B, Shao Y, Easton J, et al. Acute depletion of CTCF directly affects MYC regulation through loss of enhancer-promoter looping. Nucleic Acids Res. 2019;47:6699–713.
Hnisz D, Weintraub AS, Day DS, Valton AL, Bak RO, Li CH, et al. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science. 2016;351:1454–8.
Katainen R, Dave K, Pitkanen E, Palin K, Kivioja T, Valimaki N, et al. CTCF/cohesin-binding sites are frequently mutated in cancer. Nat Genet. 2015;47:818–21.
Chiarle R, Zhang Y, Frock RL, Lewis SM, Molinie B, Ho YJ, et al. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell. 2011;147:107–19.
Zeisig BB, Kulasekararaj AG, Mufti GJ, So CW. SnapShot: acute myeloid leukemia. Cancer Cell. 2012;22:698–e691.
Winters AC, Bernt KM. MLL-rearranged leukemias—an update on science and clinical approaches. Front Pediatr. 2017;5:4.
Rice KL, Licht JD. HOX deregulation in acute myeloid leukemia. J Clin Investig. 2007;117:865–8.
Meyer C, Kowarz E, Hofmann J, Renneville A, Zuna J, Trka J, et al. New insights to the MLL recombinome of acute leukemias. Leukemia. 2009;23:1490–9.
Kon A, Shih LY, Minamino M, Sanada M, Shiraishi Y, Nagata Y, et al. Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat Genet. 2013;45:1232–7.
Heath EM, Chan SM, Minden MD, Murphy T, Shlush LI, Schimmer AD. Biological and clinical consequences of NPM1 mutations in AML. Leukemia. 2017;31:798–807.
Brunetti L, Gundry MC, Sorcini D, Guzman AG, Huang YH, Ramabadran R, et al. Mutant NPM1 maintains the leukemic state through HOX expression. Cancer Cell. 2018;34:499–512.e499.
Wang AJ, Han Y, Jia N, Chen P, Minden MD. NPM1c impedes CTCF functions through cytoplasmic mislocalization in acute myeloid leukemia. Leukemia. 2020;34:1278–90.
Acknowledgements
We thank our colleague in the SH and YQ Labs for their comments on this paper. The authors also thank Rachael Mills for editing the paper. This work was supported by the grants from the National Institute of Health (R01DK110108, R01CA204044, R01HL141950 to SH; R01HL144712 to YQ) and the Four Diamonds Fund (SH).
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YQ and SH both conceived the idea and wrote the paper.
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Qiu, Y., Huang, S. CTCF-mediated genome organization and leukemogenesis. Leukemia 34, 2295–2304 (2020). https://doi.org/10.1038/s41375-020-0906-x
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DOI: https://doi.org/10.1038/s41375-020-0906-x
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