A mechanism for Ikaros regulation of human globin gene switching

The human β globin locus consists of an upstream LCR and functional genes arranged sequentially in the order of their expression during development: 5′‐HBE1, HBG2, HBG1, HBD, HBB‐3′. Haemoglobin switching entails the successive recruitment of these genes into an active chromatin hub (ACH). Here we show that the transcription factor Ikaros plays a major role in the formation of the β‐globin ACH, and in haemoglobin switching. In Plastic mice, where the DNA‐binding region of Ikaros is disrupted by a point mutation, there is concomitant marked down‐regulation of HBB, and up‐regulation of HBG expression. We show for the first time Ikaros and its family member Eos, bind to critical cis elements implicated in haemoglobin switching and deletional hereditary persistence of fetal haemoglobin (HPFH). Chromatin conformation capture (3C) data demonstrated that Ikaros facilitates long‐distance DNA looping between the LCR and a region upstream of HBD. This study provides new insights into the mechanism of stage‐specific assembly of the β‐globin ACH, and HPFH.

[1]  C. Chabannon,et al.  The role of Ikaros in human erythroid differentiation. , 2008, Blood.

[2]  F. Grosveld,et al.  β-Globin Active Chromatin Hub Formation in Differentiating Erythroid Cells and in p45 NF-E2 Knock-out Mice* , 2007, Journal of Biological Chemistry.

[3]  T. Townes,et al.  Differential Binding of Erythroid Krupple-like Factor to Embryonic/Fetal Globin Gene Promoters during Development* , 2006, Journal of Biological Chemistry.

[4]  S. Ng,et al.  Early hematopoietic lineage restrictions directed by Ikaros , 2006, Nature Immunology.

[5]  A. McDowall,et al.  A global role for EKLF in definitive and primitive erythropoiesis. , 2005, Blood.

[6]  S. Brenner,et al.  STAT4 is a target of the hematopoietic zinc‐finger transcription factor Ikaros in T cells , 2005, FEBS letters.

[7]  P. Navas,et al.  Synergistic and Additive Properties of the Beta-Globin Locus Control Region (LCR) Revealed by 5′HS3 Deletion Mutations: Implication for LCR Chromatin Architecture , 2005, Molecular and Cellular Biology.

[8]  Cameron S. Osborne,et al.  The Corfu δβ thalassemia deletion disrupts γ-globin gene silencing and reveals post-transcriptional regulation of HbF expression Running title: Corfu δβ thalassemia and β-globin regulation , 2005 .

[9]  M. Groudine,et al.  Proximity among distant regulatory elements at the beta-globin locus requires GATA-1 and FOG-1. , 2005, Molecular cell.

[10]  F. Grosveld,et al.  The active spatial organization of the beta-globin locus requires the transcription factor EKLF. , 2004, Genes & development.

[11]  J. Whetstine,et al.  Roles of USF, Ikaros and Sp proteins in the transcriptional regulation of the human reduced folate carrier B promoter. , 2004, The Biochemical journal.

[12]  V. Chow,et al.  The SARS coronavirus nucleocapsid protein induces actin reorganization and apoptosis in COS-1 cells in the absence of growth factors. , 2004, The Biochemical journal.

[13]  J. Strouboulis,et al.  Multiple interactions between regulatory regions are required to stabilize an active chromatin hub. , 2004, Genes & development.

[14]  A. Perkins,et al.  Widespread failure of hematolymphoid differentiation caused by a recessive niche-filling allele of the Ikaros transcription factor. , 2003, Immunity.

[15]  Suya Yang,et al.  Sequences in the Aγ–δ intergenic region are not required for stage-specific regulation of the human β-globin gene locus , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Erik Splinter,et al.  Looping and interaction between hypersensitive sites in the active beta-globin locus. , 2002, Molecular cell.

[17]  Cameron S. Osborne,et al.  Long-range chromatin regulatory interactions in vivo , 2002, Nature Genetics.

[18]  J. Seavitt,et al.  Unconventional Potentiation of Gene Expression by Ikaros* , 2002, The Journal of Biological Chemistry.

[19]  David J States,et al.  Faculty Opinions recommendation of GATA-1 binding sites mapped in the beta-globin locus by using mammalian chIp-chip analysis. , 2002 .

[20]  K. Georgopoulos.  Haematopoietic cell-fate decisions, chromatin regulation and ikaros , 2002, Nature Reviews Immunology.

[21]  M. Gerstein,et al.  GATA-1 binding sites mapped in the β-globin locus by using mammalian chIp-chip analysis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Dekker,et al.  Capturing Chromosome Conformation , 2002, Science.

[23]  A. Bank,et al.  Multiple hematopoietic defects and delayed globin switching in Ikaros null mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[24]  W. Miller,et al.  Sequences Flanking Hypersensitive Sites of the β-Globin Locus Control Region Are Required for Synergistic Enhancement , 2001, Molecular and Cellular Biology.

[25]  M. Crossley,et al.  Eos and Pegasus, Two Members of the Ikaros Family of Proteins with Distinct DNA Binding Activities* , 2000, The Journal of Biological Chemistry.

[26]  H. Erdjument-Bromage,et al.  An Ikaros-Containing Chromatin-Remodeling Complex in Adult-Type Erythroid Cells , 2000, Molecular and Cellular Biology.

[27]  A. Fisher,et al.  Targeting of Ikaros to pericentromeric heterochromatin by direct DNA binding. , 2000, Genes & development.

[28]  K. Georgopoulos,et al.  Ikaros Interactions with CtBP Reveal a Repression Mechanism That Is Independent of Histone Deacetylase Activity* , 2000, The Journal of Biological Chemistry.

[29]  F. Costantini,et al.  Developmentally distinct effects on human ε-, γ- and δ-globin levels caused by the absence or altered position of the human β-globin gene in YAC transgenic mice , 2000 .

[30]  P. Fraser,et al.  Intergenic transcription and developmental remodeling of chromatin subdomains in the human beta-globin locus. , 2000, Molecular cell.

[31]  R. Kingston,et al.  Ikaros DNA-binding proteins direct formation of chromatin remodeling complexes in lymphocytes. , 1999, Immunity.

[32]  H. Erdjument-Bromage,et al.  Tissue-specific and developmental stage-specific DNA binding by a mammalian SWI/SNF complex associated with human fetal-to-adult globin gene switching. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[33]  W. Miller,et al.  Sequences Within and Flanking Hypersensitive Sites 3 and 2 of the β-Globin Locus Control Region Required for Synergistic Versus Additive Interaction With the ε-globin Gene Promoter , 1996 .

[34]  C. Turck,et al.  The lymphoid transcription factor LyF-1 is encoded by specific, alternatively spliced mRNAs derived from the Ikaros gene. , 1994, Molecular and cellular biology.

[35]  A. Sharpe,et al.  The ikaros gene is required for the development of all lymphoid lineages , 1994, Cell.

[36]  Y. Kan,et al.  Germ-line transmission and developmental regulation of a 150-kb yeast artificial chromosome containing the human beta-globin locus in transgenic mice. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[37]  G. Stamatoyannopoulos,et al.  Transgenic mice containing a 248-kb yeast artificial chromosome carrying the human beta-globin locus display proper developmental control of human globin genes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[38]  R. W. Jones,et al.  The Corfu delta beta zero thalassemia: a small deletion acts at a distance to selectively abolish beta globin gene expression. , 1988, Blood.

[39]  F. Grosveld,et al.  Beta-globin active chromatin Hub formation in differentiating erythroid cells and in p45 NF-E2 knock-out mice. , 2007, The Journal of biological chemistry.

[40]  Cameron S. Osborne,et al.  The Corfu deltabeta thalassemia deletion disrupts gamma-globin gene silencing and reveals post-transcriptional regulation of HbF expression. , 2005, Blood.

[41]  F. Grosveld,et al.  The beta-globin nuclear compartment in development and erythroid differentiation. , 2003, Nature genetics.

[42]  Wouter de Laat,et al.  The β-globin nuclear compartment in development and erythroid differentiation , 2003, Nature Genetics.

[43]  Suya Yang,et al.  Sequences in the (A)gamma-delta intergenic region are not required for stage-specific regulation of the human beta-globin gene locus. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[44]  F. Costantini,et al.  Developmentally distinct effects on human epsilon-, gamma- and delta-globin levels caused by the absence or altered position of the human beta-globin gene in YAC transgenic mice. , 2000, Human molecular genetics.

[45]  W. Miller,et al.  Sequences within and flanking hypersensitive sites 3 and 2 of the beta-globin locus control region required for synergistic versus additive interaction with the epsilon-globin gene promoter. , 1996, Nucleic acids research.

[46]  Peter Fraser,et al.  Transcription complex stability and chromatin dynamics in vivo , 1995, Nature.