Global changes in nuclear positioning of genes and intra- and inter-domain genomic interactions that orchestrate B cell fate

The genome is folded into domains located in compartments that are either transcriptionally inert or transcriptionally permissive. Here we used genome-wide strategies to characterize domains during B cell development. Structured interaction matrix analysis showed that occupancy by the architectural protein CTCF was associated mainly with intradomain interactions, whereas sites bound by the histone acetyltransferase p300 or the transcription factors E2A or PU.1 were associated with intra- and interdomain interactions that are developmentally regulated. We identified a spectrum of genes that switched nuclear location during early B cell development. In progenitor cells, the transcriptionally inactive locus encoding early B cell factor (Ebf1) was sequestered at the nuclear lamina, which thereby preserved their multipotency. After development into the pro-B cell stage, Ebf1 and other genes switched compartments to establish new intra- and interdomain interactions associated with a B lineage–specific transcription signature.

[1]  Reza Kalhor,et al.  Genome architectures revealed by tethered chromosome conformation capture and population-based modeling , 2011, Nature Biotechnology.

[2]  B. Kee,et al.  Cell Factor Promotes B Lymphopoiesis with Reduced Interleukin 7 Responsiveness in the Absence of E 2 A , 2004 .

[3]  J. Lawrence,et al.  The three-dimensional folding of the α-globin gene domain reveals formation of chromatin globules , 2011, Nature Structural &Molecular Biology.

[4]  J. Skok,et al.  Chromosome dynamics and the regulation of V(D)J recombination , 2010, Immunological reviews.

[5]  A. Tanay,et al.  Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome , 2012, Cell.

[6]  Suchit Jhunjhunwala,et al.  Chromatin Architecture and the Generation of Antigen Receptor Diversity , 2009, Cell.

[7]  Michael D. Wilson,et al.  Waves of Retrotransposon Expansion Remodel Genome Organization and CTCF Binding in Multiple Mammalian Lineages , 2012, Cell.

[8]  Haiping Hao,et al.  Two Forms of Loops Generate the Chromatin Conformation of the Immunoglobulin Heavy-Chain Gene Locus , 2011, Cell.

[9]  M. Dawson,et al.  Cancer Epigenetics: From Mechanism to Therapy , 2012, Cell.

[10]  D. Haussler,et al.  Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. , 2005, Genome research.

[11]  A. Fisher,et al.  Dynamic repositioning of genes in the nucleus of lymphocytes preparing for cell division. , 1999, Molecular cell.

[12]  B. Steensel,et al.  Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture–on-chip (4C) , 2006, Nature Genetics.

[13]  U. Hoffmann‐Rohrer,et al.  Nuclear myosin I acts in concert with polymeric actin to drive RNA polymerase I transcription. , 2008, Genes & development.

[14]  M. Busslinger,et al.  Pax5 induces V-to-DJ rearrangements and locus contraction of the immunoglobulin heavy-chain gene. , 2004, Genes & development.

[15]  M. Leid,et al.  An Early T Cell Lineage Commitment Checkpoint Dependent on the Transcription Factor Bcl11b , 2010, Science.

[16]  Hiroshi Kawamoto,et al.  Long-term cultured E2A-deficient hematopoietic progenitor cells are pluripotent. , 2004, Immunity.

[17]  N. D. Clarke,et al.  Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells , 2008, Cell.

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

[19]  A. Feeney,et al.  E2A and EBF act in synergy with the V(D)J recombinase to generate a diverse immunoglobulin repertoire in nonlymphoid cells. , 2000, Molecular cell.

[20]  Trey Ideker,et al.  A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates the B cell fate , 2010, Nature Immunology.

[21]  J. Sedat,et al.  A direct approach to the structure of eukaryotic chromosomes. , 1978, Cold Spring Harbor symposia on quantitative biology.

[22]  Steffen Jung,et al.  Epigenetic ontogeny of the Igk locus during B cell development , 2005, Nature Immunology.

[23]  E. Liu,et al.  An Oestrogen Receptor α-bound Human Chromatin Interactome , 2009, Nature.

[24]  I. Amit,et al.  Comprehensive mapping of long range interactions reveals folding principles of the human genome , 2011 .

[25]  Raymond K. Auerbach,et al.  Extensive Promoter-Centered Chromatin Interactions Provide a Topological Basis for Transcription Regulation , 2012, Cell.

[26]  A. Corcoran.  The epigenetic role of non-coding RNA transcription and nuclear organization in immunoglobulin repertoire generation. , 2010, Seminars in immunology.

[27]  Michael S. Becker,et al.  Spatial Organization of the Mouse Genome and Its Role in Recurrent Chromosomal Translocations , 2012, Cell.

[28]  J. B. Rattner,et al.  Radial loops and helical coils coexist in metaphase chromosomes , 1985, Cell.

[29]  Bradley E. Bernstein,et al.  DNA Sequence-Dependent Compartmentalization and Silencing of Chromatin at the Nuclear Lamina , 2012, Cell.

[30]  J. R. Paulson,et al.  The structure of histone-depleted metaphase chromosomes , 1977, Cell.

[31]  Elinore M Mercer,et al.  E2A proteins maintain the hematopoietic stem cell pool and promote the maturation of myelolymphoid and myeloerythroid progenitors , 2009, Proceedings of the National Academy of Sciences.

[32]  E. Bertolino,et al.  A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation , 2012, Nature Immunology.

[33]  Roy Riblet,et al.  Subnuclear Compartmentalization of Immunoglobulin Loci During Lymphocyte Development , 2002, Science.

[34]  Tobias A. Knoch,et al.  The 3D Structure of the Immunoglobulin Heavy-Chain Locus: Implications for Long-Range Genomic Interactions , 2008, Cell.

[35]  D. Jackson,et al.  Active RNA polymerases are localized within discrete transcription "factories' in human nuclei. , 1996, Journal of cell science.

[36]  K. Pienta,et al.  A Structural Analysis of the Role of the Nuclear Matrix and DNA Loops in the Organization of the Nucleus and Chromosome , 1984, Journal of Cell Science.

[37]  Jesse R. Dixon,et al.  Topological Domains in Mammalian Genomes Identified by Analysis of Chromatin Interactions , 2012, Nature.

[38]  Roy Riblet,et al.  Visualization of looping involving the immunoglobulin heavy-chain locus in developing B cells. , 2005, Genes & development.

[39]  R. Månsson,et al.  Chromatin topology and the regulation of antigen receptor assembly. , 2012, Annual review of immunology.

[40]  Elinore M Mercer,et al.  The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor , 2011, Proceedings of the National Academy of Sciences.

[41]  Christian Münkel,et al.  Chromosome structure predicted by a polymer model , 1998 .

[42]  Yang Xu,et al.  Important Roles for E Protein Binding Sites within the Immunoglobulin κ Chain Intronic Enhancer in Activating Vκ Jκ Rearrangement , 2004, The Journal of experimental medicine.

[43]  R. Schneider,et al.  Dynamics and interplay of nuclear architecture, genome organization, and gene expression. , 2007, Genes & development.

[44]  P. Fraser,et al.  Transcription factories: genetic programming in three dimensions. , 2012, Current opinion in genetics & development.

[45]  R. Kominami,et al.  An Essential Developmental Checkpoint for Production of the T Cell Lineage , 2010, Science.

[46]  P. Flicek,et al.  Molecular maps of the reorganization of genome-nuclear lamina interactions during differentiation. , 2010, Molecular cell.

[47]  Lia S. Campos,et al.  Reprogramming of T Cells to Natural Killer–Like Cells upon Bcl11b Deletion , 2010, Science.

[48]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[49]  M. Busslinger,et al.  Locus 'decontraction' and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene , 2005, Nature Immunology.