Combinatorial Binding Leads to Diverse Regulatory Responses: Lmd Is a Tissue-Specific Modulator of Mef2 Activity

Abstract

Understanding how complex patterns of temporal and spatial expression are regulated is central to deciphering genetic programs that drive development. Gene expression is initiated through the action of transcription factors and their cofactors converging on enhancer elements leading to a defined activity. Specific constellations of combinatorial occupancy are therefore often conceptualized as rigid binding codes that give rise to a common output of spatio-temporal expression. Here, we assessed this assumption using the regulatory input of two essential transcription factors within the Drosophila myogenic network. Mutations in either Myocyte enhancing factor 2 (Mef2) or the zinc-finger transcription factor lame duck (lmd) lead to very similar defects in myoblast fusion, yet the underlying molecular mechanism for this shared phenotype is not understood. Using a combination of ChIP-on-chip analysis and expression profiling of loss-of-function mutants, we obtained a global view of the regulatory input of both factors during development. The majority of Lmd-bound enhancers are co-bound by Mef2, representing a subset of Mef2's transcriptional input during these stages of development. Systematic analyses of the regulatory contribution of both factors demonstrate diverse regulatory roles, despite their co-occupancy of shared enhancer elements. These results indicate that Lmd is a tissue-specific modulator of Mef2 activity, acting as both a transcriptional activator and repressor, which has important implications for myogenesis. More generally, this study demonstrates considerable flexibility in the regulatory output of two factors, leading to additive, cooperative, and repressive modes of co-regulation.

Jeb/Alk signalling regulates the Lame duck GLI family transcription factor in theDrosophilavisceral mesoderm

“…Studies of Lmd transcriptional activity suggest a number of shared transcription factor-binding regions with Mef2 and a function as a co-regulator of Mef2, both as an activator or repressor of myogenic specific genes (Cunha et al, 2010). Modulation of Lmd activity occurs at the post-transcriptional level, in part by regulation of its subcellular localisation (Duan and Nguyen, 2006).…”

Fear-of-intimacy mediated zinc transport controls the function of Zn-finger transcription factors involved in myogenesis

“…A candidate protein to mediate the effect of Foi in FCMs is Minc, a ZFTF that regulates a common programme of FCMs differentiation. Hence, the expression of Minc target genes sns and h (Busser et al, 2012;Cunha et al, 2010) is severely affected in foi mutants. This effect is not rescued by panmesodermal overexpression of minc ( Fig.…”

Examining Cooperative Binding of Sox2 on DC5 Regulatory Element Upon Complex Formation with Pax6 Through Excess Electron Transfer Assay

“…The complexity of an organ development is manifested through spatiotemporal expression of genes involved in development, which is tightly regulated to a large extent by the combination of transcription factors in multi-protein complexes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). In these processes, the binding affinity of transcription factors to their genetic elements, which is crucial for transcription activity, is modulated by cooperative binding: low inherent binding affinity of the individual factors is largely enhanced when they present together by their synergistic action.…”