Modularity of CHIP/LDB transcription complexes regulates cell differentiation

Transcription is the first step through which the cell operates, via its repertoire of transcription complexes, to direct cellular functions and cellular identity by generating the cell-specific transcriptome. The modularity of the composition of constituents of these complexes allows the cell to delicately regulate its transcriptome. In a recent study we have examined the effects of reducing the levels of specific transcription co-factors on the function of two competing transcription complexes, namely CHIP-AP and CHIP-PNR which regulate development of cells in the thorax of Drosophila. We found that changing the availability of these co-factors can shift the balance between these complexes leading to transition from utilization of CHIP-AP to CHIP-PNR. This is reflected in change in the expression profile of target genes, altering developmental cell fates. We propose that such a mechanism may operate in normal fly development. Transcription complexes analogous to CHIP-AP and CHIP-PNR exist in mammals and we discuss how such a shift in the balance between them may operate in normal mammalian development.

[1]  J. Jönsson,et al.  The Lim-only protein LMO2 acts as a positive regulator of erythroid differentiation. , 2007, Biochemical and biophysical research communications.

[2]  A. Haman,et al.  Protein Stability and Transcription Factor Complex Assembly Determined by the SCL-LMO2 Interaction* , 2007, Journal of Biological Chemistry.

[3]  D. Golan,et al.  Mild spherocytosis and altered red cell ion transport in protein 4. 2-null mice. , 1999, The Journal of clinical investigation.

[4]  Vikki M. Weake,et al.  Inducible gene expression: diverse regulatory mechanisms , 2010, Nature Reviews Genetics.

[5]  O. Olivieri,et al.  Membrane cation and anion transport activities in erythrocytes of hereditary spherocytosis: Effects of different membrane protein defects , 1997, American journal of hematology.

[6]  F. Müller,et al.  Developmental regulation of transcription initiation: more than just changing the actors. , 2010, Current opinion in genetics & development.

[7]  I. Boros,et al.  Genes of the Ecdysone Biosynthesis Pathway Are Regulated by the dATAC Histone Acetyltransferase Complex in Drosophila , 2010, Molecular and Cellular Biology.

[8]  M. Milán,et al.  Beadex encodes an LMO protein that regulates Apterous LIM-homeodomain activity in Drosophila wing development: a model for LMO oncogene function. , 1998, Genes & development.

[9]  G. Chinnadurai Transcriptional regulation by C-terminal binding proteins. , 2007, The international journal of biochemistry & cell biology.

[10]  A. Hägglund,et al.  Lhx2 Expression Promotes Self-Renewal of a Distinct Multipotential Hematopoietic Progenitor Cell in Embryonic Stem Cell-Derived Embryoid Bodies , 2008, PloS one.

[11]  Hong Ma,et al.  Proteasomal selection of multiprotein complexes recruited by LIM homeodomain transcription factors , 2007, Proceedings of the National Academy of Sciences.

[12]  Andrew J. Bannister,et al.  Ubiquitination-dependent cofactor exchange on LIM homeodomain transcription factors , 2022 .

[13]  Raja Jothi,et al.  Nuclear adaptor Ldb1 regulates a transcriptional program essential for the maintenance of hematopoietic stem cells , 2011, Nature Immunology.

[14]  Patrick Rodriguez,et al.  Isolation and Characterization of Hematopoietic Transcription Factor Complexes by in Vivo Biotinylation Tagging and Mass Spectrometry , 2005, Annals of the New York Academy of Sciences.

[15]  J. Botas,et al.  Conservation of the expression and function of apterous orthologs in Drosophila and mammals. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[16]  L. Sachs,et al.  Two families of Xenopus tropicalis skeletal genes display well‐conserved expression patterns with mammals in spite of their highly divergent regulatory regions , 2010, Evolution & development.

[17]  A. McMahon,et al.  T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification. , 1999, Genes & development.

[18]  T. Blauwkamp,et al.  C‐terminal‐binding protein directly activates and represses Wnt transcriptional targets in Drosophila , 2006, The EMBO journal.

[19]  R. Sharan,et al.  Transcriptional Regulation by CHIP/LDB Complexes , 2010, PLoS genetics.

[20]  I. Lemischka,et al.  Delayed differentiation in embryonic stem cells and mesodermal progenitors in the absence of CtBP2 , 2010, Mechanisms of Development.

[21]  C. Pfeifle,et al.  apterous, a gene required for imaginal disc development in Drosophila encodes a member of the LIM family of developmental regulatory proteins. , 1992, Genes & development.

[22]  A. Garcı́a-Bellido,et al.  The relative expression amounts of apterous and its co‐factor dLdb/Chip are critical for dorso‐ventral compartmentalization in the Drosophila wing , 1998, The EMBO journal.

[23]  Eric H Davidson,et al.  Modeling the dynamics of transcriptional gene regulatory networks for animal development. , 2009, Developmental biology.

[24]  Zhengquan Yu,et al.  Co-factors of LIM domains (Clims/Ldb/Nli) regulate corneal homeostasis and maintenance of hair follicle stem cells. , 2007, Developmental biology.

[25]  B. Forget,et al.  Hematologically important mutations: band 3 and protein 4.2 variants in hereditary spherocytosis. , 1997, Blood cells, molecules & diseases.

[26]  I. Boros,et al.  Transcriptional Adaptor ADA3 of Drosophila melanogaster Is Required for Histone Modification, Position Effect Variegation, and Transcription , 2007, Molecular and Cellular Biology.

[27]  Eric H Davidson,et al.  Building developmental gene regulatory networks. , 2009, Birth defects research. Part C, Embryo today : reviews.

[28]  Long-Sheng Chang,et al.  Identification of a TAL1 Target Gene Reveals a Positive Role for the LIM Domain-Binding Protein Ldb1 in Erythroid Gene Expression and Differentiation , 2003, Molecular and Cellular Biology.

[29]  R. A. Drewell,et al.  Dissecting the regulatory switches of development: lessons from enhancer evolution in Drosophila , 2010, Development.

[30]  Michael B. Eisen,et al.  A Careful Look at Binding Site Reorganization in the even-skipped Enhancers of Drosophila and Sepsids , 2008, PLoS genetics.

[31]  T. Rabbitts,et al.  Association of erythroid transcription factors: complexes involving the LIM protein RBTN2 and the zinc-finger protein GATA1. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[32]  P. Simpson,et al.  A genetic analysis of pannier, a gene necessary for viability of dorsal tissues and bristle positioning in Drosophila. , 1996, Genetics.

[33]  A. Podtelejnikov,et al.  Ssdp proteins interact with the LIM-domain-binding protein Ldb1 to regulate development , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  S. Berger The complex language of chromatin regulation during transcription , 2007, Nature.

[35]  I. Boros,et al.  The loss of histone H3 lysine 9 acetylation due to dSAGA-specific dAda2b mutation influences the expression of only a small subset of genes , 2009, Nucleic acids research.

[36]  S. Orkin,et al.  Sumoylation Regulates Interaction of FOG1 with C-terminal-binding Protein (CTBP)* , 2010, The Journal of Biological Chemistry.

[37]  P. Heitzler,et al.  Interactions between chip and the achaete/scute-daughterless heterodimers are required for pannier-driven proneural patterning. , 2000, Molecular cell.

[38]  K. Gardner,et al.  The three Rs of transcription: recruit, retain, and recycle. , 2010, Molecular cell.

[39]  P. Heitzler,et al.  Drosophila dLMO-PA isoform acts as an early activator of achaete/scute proneural expression. , 2008, Developmental biology.

[40]  John B. Thomas,et al.  Ssdp proteins bind to LIM-interacting co-factors and regulate the activity of LIM-homeodomain protein complexes in vivo , 2003, Development.

[41]  T. Rabbitts,et al.  The LIM‐only protein Lmo2 is a bridging molecule assembling an erythroid, DNA‐binding complex which includes the TAL1, E47, GATA‐1 and Ldb1/NLI proteins , 1997, The EMBO journal.

[42]  D. Dorsett,et al.  Chip, a widely expressed chromosomal protein required for segmentation and activity of a remote wing margin enhancer in Drosophila. , 1997, Genes & development.

[43]  D. Arnosti,et al.  CtBP Contributes Quantitatively to Knirps Repression Activity in an NAD Binding-Dependent Manner , 2004, Molecular and Cellular Biology.

[44]  E. Davidson Emerging properties of animal gene regulatory networks , 2010, Nature.

[45]  L. Chang,et al.  Induction of erythrocyte protein 4.2 gene expression during differentiation of murine erythroleukemia cells. , 1999, Genomics.

[46]  S. R. Wickramasinghe,et al.  An evolving NGF–Hoxd1 signaling pathway mediates development of divergent neural circuits in vertebrates , 2010, Nature Neuroscience.

[47]  D. Segal,et al.  Drosophila LIM-Only Is a Positive Regulator of Transcription During Thoracic Bristle Development , 2008, Genetics.

[48]  M. Gerstein,et al.  Variation in Transcription Factor Binding Among Humans , 2010, Science.

[49]  E. Furlong,et al.  Challenges for modeling global gene regulatory networks during development: insights from Drosophila. , 2010, Developmental biology.

[50]  Justin Crocker,et al.  A Closer Look at the eve Stripe 2 Enhancers of Drosophila and Themira , 2008, PLoS genetics.

[51]  D. Bayarsaihan SSDP1 gene encodes a protein with a conserved N-terminal FORWARD domain. , 2002, Biochimica et biophysica acta.

[52]  Rajendran Sanalkumar,et al.  Building multifunctionality into a complex containing master regulators of hematopoiesis , 2010, Proceedings of the National Academy of Sciences.

[53]  H. Westphal,et al.  LIM homeobox transcription factors integrate signaling events that control three-dimensional limb patterning and growth , 2009, Development.

[54]  Esther Bae,et al.  Functional Evolution of cis-Regulatory Modules at a Homeotic Gene in Drosophila , 2009, PLoS genetics.

[55]  G. Chinnadurai,et al.  The transcriptional corepressor CtBP: a foe of multiple tumor suppressors. , 2009, Cancer research.

[56]  C. Desplan,et al.  Deciphering the genome's regulatory code: The many languages of DNA , 2010, BioEssays : news and reviews in molecular, cellular and developmental biology.

[57]  Hong Liang,et al.  Single-stranded DNA-binding proteins regulate the abundance of LIM domain and LIM domain-binding proteins. , 2007, Genes & development.

[58]  H. Kiyonari,et al.  Ssdp 1 regulates head morphogenesis of mouse embryos by activating the Lim 1-Ldb 1 complex , 2005 .

[59]  C. M. Cohen,et al.  Human erythrocyte membrane protein band 4.2 (pallidin). , 1993, Seminars in hematology.

[60]  Ying Cai,et al.  Single-stranded DNA-binding proteins regulate the abundance and function of the LIM-homeodomain transcription factor LHX2 in pituitary cells. , 2008, Biochemical and biophysical research communications.

[61]  P. Heitzler,et al.  Drosophila C-terminal binding protein, dCtBP is required for sensory organ prepattern and sharpens proneural transcriptional activity of the GATA factor Pnr. , 2008, Developmental biology.

[62]  D. Segal,et al.  Overexpression Beadex mutations and loss-of-function heldup-a mutations in Drosophila affect the 3' regulatory and coding components, respectively, of the Dlmo gene. , 1998, Genetics.

[63]  Martin Vingron,et al.  Studying the Evolution of Promoter Sequences: A Waiting Time Problem , 2010, J. Comput. Biol..

[64]  M. Milán,et al.  Regulation of LIM homeodomain activity in vivo: a tetramer of dLDB and apterous confers activity and capacity for regulation by dLMO. , 1999, Molecular cell.

[65]  M. Biffoni,et al.  MicroRNA 223-dependent expression of LMO2 regulates normal erythropoiesis , 2009, Haematologica.

[66]  A. Ferrús,et al.  Expression of enhancers is altered in Drosophila melanogaster hybrids , 2003, Evolution & development.

[67]  Venky N. Iyer,et al.  Sepsid even-skipped Enhancers Are Functionally Conserved in Drosophila Despite Lack of Sequence Conservation , 2008, PLoS genetics.

[68]  H. Kiyonari,et al.  Ssdp1 regulates head morphogenesis of mouse embryos by activating the Lim1-Ldb1 complex , 2005, Development.

[69]  Elaine Fuchs,et al.  Lhx2 Maintains Stem Cell Character in Hair Follicles , 2006, Science.

[70]  Christine Steinhoff,et al.  The genome-wide dynamics of the binding of Ldb1 complexes during erythroid differentiation. , 2010, Genes & development.

[71]  J. Thomas,et al.  Chip and apterous physically interact to form a functional complex during Drosophila development. , 1999, Molecular cell.

[72]  H. Westphal,et al.  Role of Ldb1 in Adult Intestinal Homeostasis , 2009, International journal of biological sciences.

[73]  Justin Crocker,et al.  Evolution Acts on Enhancer Organization to Fine-Tune Gradient Threshold Readouts , 2008, PLoS biology.