Cofactor Binding Evokes Latent Differences in DNA Binding Specificity Between Hox Proteins

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Dec 14

PMID 22153072

Citations 285

Authors

Matthew Slattery

Todd Riley

Peng Liu

Namiko Abe

Pilar Gomez-Alcala

Iris Dror

Tianyin Zhou

Remo Rohs

Barry Honig

Harmen J Bussemaker

Richard S Mann

Affiliations

Soon will be listed here.

Abstract

Members of transcription factor families typically have similar DNA binding specificities yet execute unique functions in vivo. Transcription factors often bind DNA as multiprotein complexes, raising the possibility that complex formation might modify their DNA binding specificities. To test this hypothesis, we developed an experimental and computational platform, SELEX-seq, that can be used to determine the relative affinities to any DNA sequence for any transcription factor complex. Applying this method to all eight Drosophila Hox proteins, we show that they obtain novel recognition properties when they bind DNA with the dimeric cofactor Extradenticle-Homothorax (Exd). Exd-Hox specificities group into three main classes that obey Hox gene collinearity rules and DNA structure predictions suggest that anterior and posterior Hox proteins prefer DNA sequences with distinct minor groove topographies. Together, these data suggest that emergent DNA recognition properties revealed by interactions with cofactors contribute to transcription factor specificities in vivo.

Citing Articles

Ambivalent partnership of the Drosophila posterior class Hox protein Abdominal-B with Extradenticle and Homothorax.

Curt J, Martin P, Foronda D, Hudry B, Kannan R, Shetty S PLoS Genet. 2025; 21(1):e1011355.

PMID: 39804927 PMC: 11759358. DOI: 10.1371/journal.pgen.1011355.

NKX2.2 and KLF4 cooperate to regulate α-cell identity.

Brooks E, Casey M, Wells K, Liu T, Van Orman M, Sussel L Genes Dev. 2025; 39(3-4):242-260.

PMID: 39797760 PMC: 11789634. DOI: 10.1101/gad.352193.124.

Experimental approaches to investigate biophysical interactions between homeodomain transcription factors and DNA.

Mekkaoui F, Drewell R, Dresch J, Spratt D Biochim Biophys Acta Gene Regul Mech. 2024; 1868(1):195074.

PMID: 39644990 PMC: 11832328. DOI: 10.1016/j.bbagrm.2024.195074.

Identification of co-localised transcription factors based on paired motifs analysis.

Liu L, Han L, Han K, Zhang Z, Zhang H, Zhang L IET Syst Biol. 2024; 18(6):238-249.

PMID: 39588827 PMC: 11665839. DOI: 10.1049/syb2.12104.

RLS-associated MEIS transcription factors control distinct processes in human neural stem cells.

Kittke V, Zhao C, Lam D, Harrer P, Krezel W, Schormair B Sci Rep. 2024; 14(1):28986.

PMID: 39578497 PMC: 11584712. DOI: 10.1038/s41598-024-80266-9.

References

Gebelein B, McKay D, Mann R . Direct integration of Hox and segmentation gene inputs during Drosophila development. Nature. 2004; 431(7009):653-9. DOI: 10.1038/nature02946. View

Zhao J, Lazzarini R, Pick L . The mouse Hox-1.3 gene is functionally equivalent to the Drosophila Sex combs reduced gene. Genes Dev. 1993; 7(3):343-54. DOI: 10.1101/gad.7.3.343. View

Hueber S, Weiller G, Djordjevic M, Frickey T . Improving Hox protein classification across the major model organisms. PLoS One. 2010; 5(5):e10820. PMC: 2876039. DOI: 10.1371/journal.pone.0010820. View

Lutz B, Lu H, Eichele G, Miller D, Kaufman T . Rescue of Drosophila labial null mutant by the chicken ortholog Hoxb-1 demonstrates that the function of Hox genes is phylogenetically conserved. Genes Dev. 1996; 10(2):176-84. DOI: 10.1101/gad.10.2.176. View

Cao Y, Yao Z, Sarkar D, Lawrence M, Sanchez G, Parker M . Genome-wide MyoD binding in skeletal muscle cells: a potential for broad cellular reprogramming. Dev Cell. 2010; 18(4):662-74. PMC: 2910615. DOI: 10.1016/j.devcel.2010.02.014. View

Taghli-Lamallem O, Gallet A, Leroy F, Malapert P, Vola C, Kerridge S . Direct interaction between Teashirt and Sex combs reduced proteins, via Tsh's acidic domain, is essential for specifying the identity of the prothorax in Drosophila. Dev Biol. 2007; 307(1):142-51. DOI: 10.1016/j.ydbio.2007.04.028. View

Gaulton K, Nammo T, Pasquali L, Simon J, Giresi P, Fogarty M . A map of open chromatin in human pancreatic islets. Nat Genet. 2010; 42(3):255-9. PMC: 2828505. DOI: 10.1038/ng.530. View

McGinnis N, Kuziora M, McGinnis W . Human Hox-4.2 and Drosophila deformed encode similar regulatory specificities in Drosophila embryos and larvae. Cell. 1990; 63(5):969-76. DOI: 10.1016/0092-8674(90)90500-e. View

Noyes M, Christensen R, Wakabayashi A, Stormo G, Brodsky M, Wolfe S . Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites. Cell. 2008; 133(7):1277-89. PMC: 2478728. DOI: 10.1016/j.cell.2008.05.023. View

10.

Chan S, Jaffe L, Capovilla M, Botas J, Mann R . The DNA binding specificity of Ultrabithorax is modulated by cooperative interactions with extradenticle, another homeoprotein. Cell. 1994; 78(4):603-15. DOI: 10.1016/0092-8674(94)90525-8. View

11.

Joshi R, Passner J, Rohs R, Jain R, Sosinsky A, Crickmore M . Functional specificity of a Hox protein mediated by the recognition of minor groove structure. Cell. 2007; 131(3):530-43. PMC: 2709780. DOI: 10.1016/j.cell.2007.09.024. View

12.

Li X, McGinnis W . Activity regulation of Hox proteins, a mechanism for altering functional specificity in development and evolution. Proc Natl Acad Sci U S A. 1999; 96(12):6802-7. PMC: 21996. DOI: 10.1073/pnas.96.12.6802. View

13.

LEWIS E . A gene complex controlling segmentation in Drosophila. Nature. 1978; 276(5688):565-70. DOI: 10.1038/276565a0. View

14.

Lu Q, Kamps M . Heterodimerization of Hox proteins with Pbx1 and oncoprotein E2a-Pbx1 generates unique DNA-binding specifities at nucleotides predicted to contact the N-terminal arm of the Hox homeodomain--demonstration of Hox-dependent targeting of E2a-Pbx1 in vivo. Oncogene. 1997; 14(1):75-83. DOI: 10.1038/sj.onc.1200799. View

15.

Zykovich A, Korf I, Segal D . Bind-n-Seq: high-throughput analysis of in vitro protein-DNA interactions using massively parallel sequencing. Nucleic Acids Res. 2009; 37(22):e151. PMC: 2794170. DOI: 10.1093/nar/gkp802. View

16.

Piper D, Batchelor A, Chang C, Cleary M, Wolberger C . Structure of a HoxB1-Pbx1 heterodimer bound to DNA: role of the hexapeptide and a fourth homeodomain helix in complex formation. Cell. 1999; 96(4):587-97. DOI: 10.1016/s0092-8674(00)80662-5. View

17.

Wunderlich Z, Mirny L . Different gene regulation strategies revealed by analysis of binding motifs. Trends Genet. 2009; 25(10):434-40. PMC: 3697852. DOI: 10.1016/j.tig.2009.08.003. View

18.

Alexander T, Nolte C, Krumlauf R . Hox genes and segmentation of the hindbrain and axial skeleton. Annu Rev Cell Dev Biol. 2009; 25:431-56. DOI: 10.1146/annurev.cellbio.042308.113423. View

19.

Gehring W, Qian Y, Billeter M, Furukubo-Tokunaga K, Schier A, Resendez-Perez D . Homeodomain-DNA recognition. Cell. 1994; 78(2):211-23. DOI: 10.1016/0092-8674(94)90292-5. View

20.

Zhao Y, Granas D, Stormo G . Inferring binding energies from selected binding sites. PLoS Comput Biol. 2009; 5(12):e1000590. PMC: 2777355. DOI: 10.1371/journal.pcbi.1000590. View