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Cohesin Mediates Chromatin Interactions That Regulate Mammalian β-globin Expression*

Open AccessPublished:March 29, 2011DOI:https://doi.org/10.1074/jbc.M110.207365
      The β-globin locus undergoes dynamic chromatin interaction changes in differentiating erythroid cells that are thought to be important for proper globin gene expression. However, the underlying mechanisms are unclear. The CCCTC-binding factor, CTCF, binds to the insulator elements at the 5′ and 3′ boundaries of the locus, but these sites were shown to be dispensable for globin gene activation. We found that, upon induction of differentiation, cohesin and the cohesin loading factor Nipped-B-like (Nipbl) bind to the locus control region (LCR) at the CTCF insulator and distal enhancer regions as well as at the specific target globin gene that undergoes activation upon differentiation. Nipbl-dependent cohesin binding is critical for long-range chromatin interactions, both between the CTCF insulator elements and between the LCR distal enhancer and the target gene. We show that the latter interaction is important for globin gene expression in vivo and in vitro. Furthermore, the results indicate that such cohesin-mediated chromatin interactions associated with gene regulation are sensitive to the partial reduction of Nipbl caused by heterozygous mutation. This provides the first direct evidence that Nipbl haploinsufficiency affects cohesin-mediated chromatin interactions and gene expression. Our results reveal that dynamic Nipbl/cohesin binding is critical for developmental chromatin organization and the gene activation function of the LCR in mammalian cells.

      Introduction

      An emerging aspect of epigenetics is the three-dimensional organization of chromatin determined by long-distance chromatin interactions. Evidence suggests that this has critical influence on the nuclear positioning and distal regulatory element-promoter interactions important for developmentally coordinated and cell type-specific gene expression (
      • Schneider R.
      • Grosschedl R.
      ). However, our knowledge of the factors involved in these processes is limited.
      The β-globin locus has been characterized extensively as a prime example of such chromatin organization. The 80-kb locus is flanked by 5′ and 3′ insulator elements that interact to form a large chromatin loop mediated by the CCCTC-binding factor (CTCF)
      The abbreviations used are: CTCF
      CCCTC-binding factor
      LCR
      locus control region
      Nipbl
      Nipped-B-like
      DMSO
      dimethyl sulfoxide
      E11.5
      embryonic day 11.5
      ChIP
      chromatin immunoprecipitation
      IP
      immunoprecipitation
      Q-PCR
      quantitative PCR
      3C
      chromosome conformation capture
      Ct
      threshold cycles
      MEL
      mouse erythroleukemia
      NF-E2
      NF-erythroid-derived 2
      HS
      DNase I hypersensitive site
      SMC1
      structural maintenance of chromosomes 1.
      (
      • Splinter E.
      • Heath H.
      • Kooren J.
      • Palstra R.J.
      • Klous P.
      • Grosveld F.
      • Galjart N.
      • de Laat W.
      ). The interactions between the distal enhancer within the locus control region (LCR) and the developmental stage-specific β-globin genes strongly correlate with proper activation (
      • Palstra R.J.
      • Tolhuis B.
      • Splinter E.
      • Nijmeijer R.
      • Grosveld F.
      • de Laat W.
      ,
      • Carter D.
      • Chakalova L.
      • Osborne C.S.
      • Dai Y.F.
      • Fraser P.
      ). Despite the identification of transcriptional activators, such as LIM domain binding 1 (
      • Song S.H.
      • Hou C.
      • Dean A.
      ), that critically influence this process, the molecular mechanism responsible for this bridging was not well understood (
      • Bulger M.
      • Groudine M.
      ).
      Cohesin is a conserved protein complex essential for sister chromatid cohesion and proper chromosome segregation during cell division (
      • Wood A.J.
      • Severson A.F.
      • Meyer B.J.
      ). It consists of SMC1, SMC3, Rad21 (or Scc1), and SA (or Scc3). Chromatin binding of cohesin requires the loading factor Nipbl (Scc2 or delangin). Recent evidence indicates that cohesin also plays a role in gene regulation. A major mechanism of the role of cohesin in gene regulation is thought to involve CTCF (
      • Wendt K.S.
      • Peters J.M.
      ). CTCF is a zinc finger DNA-binding protein that acts as a transcriptional activator/repressor as well as an insulator (
      • Zlatanova J.
      • Caiafa P.
      ). CTCF recruits cohesin to many of its binding sites, and over 70% of cohesin binding sites identified in unique regions in the mouse and human genome overlap with those of CTCF (
      • Wendt K.S.
      • Peters J.M.
      ). Cohesin depletion impairs CTCF-mediated insulator function and chromatin loop formation (
      • Hadjur S.
      • Williams L.M.
      • Ryan N.K.
      • Cobb B.S.
      • Sexton T.
      • Fraser P.
      • Fisher A.G.
      • Merkenschlager M.
      ,
      • Mishiro T.
      • Ishihara K.
      • Hino S.
      • Tsutsumi S.
      • Aburatani H.
      • Shirahige K.
      • Kinoshita Y.
      • Nakao M.
      ,
      • Nativio R.
      • Wendt K.S.
      • Ito Y.
      • Huddleston J.E.
      • Uribe-Lewis S.
      • Woodfine K.
      • Krueger C.
      • Reik W.
      • Peters J.M.
      • Murrell A.
      ). These studies suggested that cohesin plays an architectural role in chromatin domain organization in the context of CTCF binding sites, which is important for developmental gene regulation. Recent studies, however, also provided evidence for CTCF-independent cohesin recruitment to various genomic regions, suggesting different roles of cohesin in gene regulation (
      • Kagey M.H.
      • Newman J.J.
      • Bilodeau S.
      • Zhan Y.
      • Orlando D.A.
      • van Berkum N.L.
      • Ebmeier C.C.
      • Goossens J.
      • Rahl P.B.
      • Levine S.S.
      • Taatjes D.J.
      • Dekker J.
      • Young R.A.
      ,
      • Schmidt D.
      • Schwalie P.C.
      • Ross-Innes C.S.
      • Hurtado A.
      • Brown G.D.
      • Carroll J.S.
      • Flicek P.
      • Odom D.T.
      ,
      • Zeng W.
      • de Greef J.C.
      • Chen Y.Y.
      • Chien R.
      • Kong X.
      • Gregson H.C.
      • Winokur S.T.
      • Pyle A.
      • Robertson K.D.
      • Schmiesing J.A.
      • Kimonis V.E.
      • Balog J.
      • Frants R.R.
      • Ball Jr., A.R.
      • Lock L.F.
      • Donovan P.J.
      • van der Maarel S.M.
      • Yokomori K.
      ). However, the extent of the involvement of cohesin in gene regulation is not fully understood. Here we report the identification of cohesin as an important mechanistic mediator of chromatin interactions at the β-globin locus. We found that cohesin and Nipbl bind not only to the expected CTCF insulator sites but also at other regions of the β-globin LCR as well as at active globin genes. Their binding occurs in a cell type-specific and differentiation-induced manner, which is critical for LCR-globin gene interactions and globin gene expression. Our results demonstrate that cohesin/Nipbl is an integral structural component that mediates gene regulation via chromatin interactions at the β-globin locus, which provides a paradigm for CTCF insulator-dependent and independent functions of cohesin in gene regulation.

      DISCUSSION

      In this study, we examined the role of cohesin and the cohesin loading factor Nipbl in β-globin gene expression in mouse and human cells. We demonstrate the induction of Nipbl and cohesin binding during cellular differentiation at the β-globin locus. Cohesin/Nipbl binding is induced not only at CTCF insulator sites but also at other regions of the LCR and at active globin genes in an apparently CTCF-independent manner. A deficiency of cohesin or Nipbl disrupted the LCR enhancer-promoter interactions and inhibited gene expression. This strongly supports the critical role of cohesin/Nipbl in chromatin interaction-mediated gene regulation at the β-globin locus (Fig. 4). Our results provide important insight into the role of mammalian cohesin in LCR function.
      Figure thumbnail gr4
      FIGURE 4A schematic diagram of cohesin function at the β-globin locus. In the silent β-globin locus of erythroid progenitors, cohesin and CTCF bind at the HS5 and 3′HS1 insulator sites, setting the boundaries for later activation. When the locus becomes active, more transcription factors are recruited, and they can strengthen the chromatin interactions for optimal gene expression. Cohesin has a dual function, as it mediates both gene-enhancer interactions and boundary insulator interactions.

      Cell Type-specific and Differentiation-induced Cohesin Binding Involves Specific Induction of Nipbl Binding

      In Saccharomyces cerevisiae, the relationship between cohesin and the cohesin loading factor Scc2 (Nipbl homolog) binding sites is controversial. One study demonstrated the complete colocalization of cohesin with Scc2 (
      • Kogut I.
      • Wang J.
      • Guacci V.
      • Mistry R.K.
      • Megee P.C.
      ), whereas another study indicated that ongoing transcription moves cohesin from its initial loading sites where Scc2 resides to converging intergenic sites (
      • Lengronne A.
      • Katou Y.
      • Mori S.
      • Yokobayashi S.
      • Kelly G.P.
      • Itoh T.
      • Watanabe Y.
      • Shirahige K.
      • Uhlmann F.
      ). Furthermore, cohesin relocalization associated with transcriptional changes appears to be Scc2-independent (
      • Bausch C.
      • Noone S.
      • Henry J.M.
      • Gaudenz K.
      • Sanderson B.
      • Seidel C.
      • Gerton J.L.
      ). In mammalian cells, although Nipbl was found to colocalize with a subset of cohesin binding sites in mouse embryonic stem cells (
      • Kagey M.H.
      • Newman J.J.
      • Bilodeau S.
      • Zhan Y.
      • Orlando D.A.
      • van Berkum N.L.
      • Ebmeier C.C.
      • Goossens J.
      • Rahl P.B.
      • Levine S.S.
      • Taatjes D.J.
      • Dekker J.
      • Young R.A.
      ), it was unclear how Nipbl binding is altered in different cell types and differentiation stages and how it relates to changes in cohesin binding. Our results show that Nipbl binding is induced at cohesin binding sites and is required for cohesin binding during gene activation, which is clearly distinct from what was observed in yeast, indicating that Nipbl plays an important role in differentiation-induced cohesin binding in mammals. Importantly, our results provide the first evidence that partial reduction of Nipbl by heterozygous mutation is sufficient to cause alteration of cohesin-mediated chromatin interactions. This may provide important mechanistic insight into Cornelia de Lange syndrome, a human developmental disorder linked to Nipbl haploinsufficiency (
      • Liu J.
      • Krantz I.D.
      ).

      Role of Cohesin in β-globin Gene Expression

      Although the β-globin locus was shown to undergo dynamic chromatin interaction changes during differentiation, the molecular mechanism and significance of these chromatin interactions were unclear. Although CTCF mediates the HS5 and 3′HS1 insulator interaction, deletion of CTCF sites failed to affect β-globin gene expression, and other HS sites in the LCR are required for proper β-globin expression (
      • Splinter E.
      • Heath H.
      • Kooren J.
      • Palstra R.J.
      • Klous P.
      • Grosveld F.
      • Galjart N.
      • de Laat W.
      ,
      • Alami R.
      • Bender M.A.
      • Feng Y.Q.
      • Fiering S.N.
      • Hug B.A.
      • Ley T.J.
      • Groudine M.
      • Bouhassira E.E.
      ,
      • Bender M.A.
      • Byron R.
      • Ragoczy T.
      • Telling A.
      • Bulger M.
      • Groudine M.
      ,
      • Bender M.A.
      • Reik A.
      • Close J.
      • Telling A.
      • Epner E.
      • Fiering S.
      • Hardison R.
      • Groudine M.
      ,
      • Farrell C.M.
      • Grinberg A.
      • Huang S.P.
      • Chen D.
      • Pichel J.G.
      • Westphal H.
      • Felsenfeld G.
      ). Our results indicate that cohesin binds not only to CTCF sites but also to other HS sites in the LCR and indeed mediates chromatin interactions both at the CTCF insulator sites and at enhancer regions. This role of cohesin is conserved in mouse and human cells. Our comparison of CTCF and cohesin depletion in human K562 cells strongly suggests that cohesin promotes β-globin gene expression by mediating the interaction between non-CTCF sites in the LCR and specific globin target genes. Interestingly, a recent study using the same cell line showed that CTCF depletion has an effect on Gγ expression, although the effect on chromatin interactions was not examined inside of the β-globin locus (
      • Hou C.
      • Dale R.
      • Dean A.
      ). This apparent discrepancy may be due to different methods and/or durations of CTCF depletion, which was shorter in our study. Nevertheless, under our CTCF depletion conditions that affected cohesin binding at the insulator sites and the insulator interaction, there was no effect on the enhancer-target gene interaction and Gγ expression. Thus, our results highlight the distinction between CTCF insulator-dependent and independent functions of cohesin at this locus.

      Multiple Effects of Cohesin in Gene Expression

      Cohesin and cohesin-associated factors affect gene expression in different contexts in multiple organisms. It was first reported in S. cerevisiae that cohesin affects boundary function at the HMR locus (
      • Donze D.
      • Adams C.R.
      • Rine J.
      • Kamakaka R.T.
      ). Similarly, cohesin interferes with the distal enhancer-promoter interactions for the cut and ultrabithorax genes in Drosophila (
      • Rollins R.A.
      • Korom M.
      • Aulner N.
      • Martens A.
      • Dorsett D.
      ). In mammalian cells, RNA polymerase II transcription has a tendency to stall at cohesin/CTCF binding sites (
      • Wada Y.
      • Ohta Y.
      • Xu M.
      • Tsutsumi S.
      • Minami T.
      • Inoue K.
      • Komura D.
      • Kitakami J.
      • Oshida N.
      • Papantonis A.
      • Izumi A.
      • Kobayashi M.
      • Meguro H.
      • Kanki Y.
      • Mimura I.
      • Yamamoto K.
      • Mataki C.
      • Hamakubo T.
      • Shirahige K.
      • Aburatani H.
      • Kimura H.
      • Kodama T.
      • Cook P.R.
      • Ihara S.
      ), suggesting that the presence of cohesin may serve as a roadblock for transcription. Perhaps to negate this interfering effect of cohesin, yeast cohesins move out of gene regions as transcription is activated and accumulate in regions of transcriptional convergence (
      • Lengronne A.
      • Katou Y.
      • Mori S.
      • Yokobayashi S.
      • Kelly G.P.
      • Itoh T.
      • Watanabe Y.
      • Shirahige K.
      • Uhlmann F.
      ,
      • Bausch C.
      • Noone S.
      • Henry J.M.
      • Gaudenz K.
      • Sanderson B.
      • Seidel C.
      • Gerton J.L.
      ). In addition, cohesin/Nipbl may play an active role in gene silencing. A recent study reported the interaction of Nipbl with histone deacetylases, indicative of its role in promoting deacetylation and transcriptional silencing (
      • Jahnke P.
      • Xu W.
      • Wülling M.
      • Albrecht M.
      • Gabriel H.
      • Gillessen-Kaesbach G.
      • Kaiser F.J.
      ). We previously found the binding of cohesin to heterochromatic repeat regions in human cells, which is Nipbl- dependent but CTCF-independent, also suggesting its link to repressive chromatin organization and gene silencing (
      • Zeng W.
      • de Greef J.C.
      • Chen Y.Y.
      • Chien R.
      • Kong X.
      • Gregson H.C.
      • Winokur S.T.
      • Pyle A.
      • Robertson K.D.
      • Schmiesing J.A.
      • Kimonis V.E.
      • Balog J.
      • Frants R.R.
      • Ball Jr., A.R.
      • Lock L.F.
      • Donovan P.J.
      • van der Maarel S.M.
      • Yokomori K.
      ).
      In contrast, our current results demonstrate that cohesin recruitment is part of a differentiation-induced gene activation process in which cohesin mediates distal enhancer-target gene interactions. In this context, cohesin does not appear to interfere with transcription. This is in agreement with other studies that suggest that cohesin binding promotes gene expression. Many cohesin binding sites coincide with RNA polymerase II in transcriptionally active gene regions in Drosophila (
      • Misulovin Z.
      • Schwartz Y.B.
      • Li X.Y.
      • Kahn T.G.
      • Gause M.
      • MacArthur S.
      • Fay J.C.
      • Eisen M.B.
      • Pirrotta V.
      • Biggin M.D.
      • Dorsett D.
      ), and genetic analysis suggested that the cohesin subunit Rad21 and Nipped-B (Drosophila Nipbl homolog) have trithorax (trxG) function important for hedgehog gene expression (
      • Hallson G.
      • Syrzycka M.
      • Beck S.A.
      • Kennison J.A.
      • Dorsett D.
      • Page S.L.
      • Hunter S.M.
      • Keall R.
      • Warren W.D.
      • Brock H.W.
      • Sinclair D.A.
      • Honda B.M.
      ). A significant overlap between the binding of the mediator complex and cohesin in the enhancer and promoter regions of active genes was observed in mouse embryonic stem cells (
      • Kagey M.H.
      • Newman J.J.
      • Bilodeau S.
      • Zhan Y.
      • Orlando D.A.
      • van Berkum N.L.
      • Ebmeier C.C.
      • Goossens J.
      • Rahl P.B.
      • Levine S.S.
      • Taatjes D.J.
      • Dekker J.
      • Young R.A.
      ). A similar overlap was found between tissue-specific transcription factors and cohesin at non-CTCF sites in human cancer cells (
      • Schmidt D.
      • Schwalie P.C.
      • Ross-Innes C.S.
      • Hurtado A.
      • Brown G.D.
      • Carroll J.S.
      • Flicek P.
      • Odom D.T.
      ). These studies collectively suggest that there are different modes by which cohesin exerts its effect on transcription, resulting in gene insulation, repression, or activation.

      Specificity of Cohesin Function in Gene Regulation

      How are the functional specificities of cohesin determined? This may be dictated by chromatin context and how cohesin is recruited. Although CTCF recruits cohesin to its binding sites, cohesin recruitment to D4Z4 heterochromatin requires H3K9me3 and HP1γ (
      • Zeng W.
      • de Greef J.C.
      • Chen Y.Y.
      • Chien R.
      • Kong X.
      • Gregson H.C.
      • Winokur S.T.
      • Pyle A.
      • Robertson K.D.
      • Schmiesing J.A.
      • Kimonis V.E.
      • Balog J.
      • Frants R.R.
      • Ball Jr., A.R.
      • Lock L.F.
      • Donovan P.J.
      • van der Maarel S.M.
      • Yokomori K.
      ). The cohesin loading factor Nipbl, rather than cohesin itself, interacts with HP1 (
      • Zeng W.
      • de Greef J.C.
      • Chen Y.Y.
      • Chien R.
      • Kong X.
      • Gregson H.C.
      • Winokur S.T.
      • Pyle A.
      • Robertson K.D.
      • Schmiesing J.A.
      • Kimonis V.E.
      • Balog J.
      • Frants R.R.
      • Ball Jr., A.R.
      • Lock L.F.
      • Donovan P.J.
      • van der Maarel S.M.
      • Yokomori K.
      ,
      • Lechner M.S.
      • Schultz D.C.
      • Negorev D.
      • Maul G.G.
      • Rauscher 3rd, F.J.
      ). Nipbl was also shown to interact with the mediator complex, although whether mediator is required for Nipbl and cohesin recruitment has not been examined (
      • Kagey M.H.
      • Newman J.J.
      • Bilodeau S.
      • Zhan Y.
      • Orlando D.A.
      • van Berkum N.L.
      • Ebmeier C.C.
      • Goossens J.
      • Rahl P.B.
      • Levine S.S.
      • Taatjes D.J.
      • Dekker J.
      • Young R.A.
      ). In contrast, cohesin, and not Nipbl, binds to CTCF (
      • Zeng W.
      • de Greef J.C.
      • Chen Y.Y.
      • Chien R.
      • Kong X.
      • Gregson H.C.
      • Winokur S.T.
      • Pyle A.
      • Robertson K.D.
      • Schmiesing J.A.
      • Kimonis V.E.
      • Balog J.
      • Frants R.R.
      • Ball Jr., A.R.
      • Lock L.F.
      • Donovan P.J.
      • van der Maarel S.M.
      • Yokomori K.
      ,
      • Stedman W.
      • Kang H.
      • Lin S.
      • Kissil J.L.
      • Bartolomei M.S.
      • Lieberman P.M.
      ,
      • Rubio E.D.
      • Reiss D.J.
      • Welcsh P.L.
      • Disteche C.M.
      • Filippova G.N.
      • Baliga N.S.
      • Aebersold R.
      • Ranish J.A.
      • Krumm A.
      ). At the β-globin locus, it was previously found that the NF-E2 subunit p18 interacts with the cohesin components SMC1 and Rad21 (
      • Brand M.
      • Ranish J.A.
      • Kummer N.T.
      • Hamilton J.
      • Igarashi K.
      • Francastel C.
      • Chi T.H.
      • Crabtree G.R.
      • Aebersold R.
      • Groudine M.
      ). Thus, cohesin interaction with NF-E2 may contribute to the differentiation-induced cohesin binding to the HS2 and/or globin gene promoter. In addition, crucial β-globin gene activators such as erythroid kruppel-like factor, GATA-binding factor 1, and LIM domain binding 1, which also affect chromatin interactions (
      • Song S.H.
      • Hou C.
      • Dean A.
      ,
      • Drissen R.
      • Palstra R.J.
      • Gillemans N.
      • Splinter E.
      • Grosveld F.
      • Philipsen S.
      • de Laat W.
      ,
      • Vakoc C.R.
      • Letting D.L.
      • Gheldof N.
      • Sawado T.
      • Bender M.A.
      • Groudine M.
      • Weiss M.J.
      • Dekker J.
      • Blobel G.A.
      ), may contribute to the recruitment of cohesin.
      We hypothesize that through different mechanisms, cohesin is recruited to certain chromatin regions to stabilize and/or facilitate their interaction to ensure proper gene expression during development. In that sense, cohesin may contribute to the “epigenetic memory” of chromatin interactions in each cell type and differentiation stage. Further studies will be necessary to address how binding and functional specificities of cohesin are determined and to characterize the gene regulatory networks involving cohesin.

      Acknowledgments

      We thank Drs. Ann Dean, Paolo Sassone-Corsi, and Peter Verrijzer for critical reading of the manuscript.

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