Specific Protein-Protein Interaction between Basic Helix-Loop-Helix Transcription Factors and Homeoproteins of the Pitx Family

Abstract

Homeoproteins and basic helix-loop-helix (bHLH) transcription factors are known for their critical role in development and cellular differentiation. The pituitary pro-opiomelanocortin (POMC) gene is a target for factors of both families. Indeed, pituitary-specific transcription of POMC depends on the action of the homeodomain-containing transcription factor Pitx1 and of bHLH heterodimers containing NeuroD1. We now show lineage-restricted expression of NeuroD1 in pituitary corticotroph cells and a direct physical interaction between bHLH heterodimers and Pitx1 that results in transcriptional synergism. The interaction between the bHLH and homeodomains is restricted to ubiquitous (class A) bHLH and to the Pitx subfamily. Since bHLH heterodimers interact with Pitx factors through their ubiquitous moiety, this mechanism may be implicated in other developmental processes involving bHLH factors, such as neurogenesis and myogenesis.Cell-specific transcription results from complex molecular interactions that involve the synergistic action of multiple transcription factors. Taken together, these interactions provide the molecular basis for the complex program of cell differentiation and development. Factors of two classes of transcription factors often involved in developmental processes, the homeodomain (HD) and the basic helix-loop-helix (bHLH) factors, were found to form the basis for cell-specific transcription of pituitary pro-opiomelanocortin (POMC) gene expression. We have used this system to define the molecular mechanism by which these two classes of transcription factors can synergistically interact to control transcription. More specifically, our studies reveal a specific interaction between the HD of the Pitx (Ptx) subfamily of homeobox proteins and the widely expressed class A bHLH transcription factors.

Nuclear Factor of Activated T Cells Regulates Transcription of the Surfactant Protein D Gene (Sftpd) via Direct Interaction with Thyroid Transcription Factor-1 in Lung Epithelial Cells

“…Nonetheless, transcriptional synergism due to physical interaction of homeodomains with other transcription factors is well documented. For example, Pitx HD interacts with basic helix-loop-helix proteins on the proopiomelanocortin promoter, whereas Pdx1 HD interacts with Pan1 on the rat insulin promoter (8,73).…”

Rb Enhances p160/SRC Coactivator-dependent Activity of Nuclear Receptors and Hormone Responsiveness

“…1, A (lanes 2, and 4) and B (lane 6)) was ascribed to the Ebox neuro and to basic helix-loop-helix factors (25). Prior work indicated that the NurRE and the cognate Nur factors contribute to basal activity as well as to POMC promoter responsiveness to the hypothalamic hormone CRH (5, 7), whereas the Ebox neuro contributes to basal activity (26,27).…”

Geminin's Double Life: Chromatin Connections that Regulate Transcription at the Transition from Proliferation to Differentiation

“…There is an extensive precedent for functional cooperativity between bHLH and homeodomain proteins in regulating developmental processes: for example, during neurogenesis and retinogenesis bHLH proteins drive neuronal fate and differentiation while homeodomain protein activities specify particular cellular subtypes. 9,[41][42][43][44][45] This can involve direct transcriptional coordination between homeodomain and bHLH proteins bound to adjacent sites in target gene enhancers. 46 Therefore, it will be interesting to determine whether Geminin's interactions with both homeodomain proteins and SWI/SNF provide a dual negative regulatory mechanism at target genes coordinately regulated by bHLH, homeodomain, and SWI/SNF protein complexes.…”