Complex cis-regulatory landscape of the insulin receptor gene underlies the broad expression of a central signaling regulator

Abstract

Insulin signaling plays key roles in development, growth and metabolism through dynamic control of glucose uptake, global protein translation and transcriptional regulation. Altered levels of insulin signaling are known to play key roles in development and disease, yet the molecular basis of such differential signaling remains obscure. Expression of the insulin receptor (InR) gene itself appears to play an important role, but the nature of the molecular wiring controlling InR transcription has not been elucidated. We characterized the regulatory elements driving Drosophila InR expression and found that the generally broad expression of this gene is belied by complex individual switch elements, the dynamic regulation of which reflects direct and indirect contributions of FOXO, EcR, Rbf and additional transcription factors through redundant elements dispersed throughout ∼40 kb of non-coding regions. The control of InR transcription in response to nutritional and tissuespecific inputs represents an integration of multiple cis-regulatory elements, the structure and function of which may have been sculpted by evolutionary selection to provide a highly tailored set of signaling responses on developmental and tissue-specific levels.

Damage-responsive elements in Drosophila regeneration

“…Since enhancers can be used in a context-dependent manner (Nègre et al 2011;McKay and Lieb 2013;Wei et al 2016;Erceg et al 2017), we assessed whether DRREs are involved in other developmental events, regardless of their specific role in wing disc regeneration. We took advantage of chromatin accessibility data from different tissues and stages of fly development (McKay and Lieb 2013).…”

Characterization of dFOXO binding sites upstream of the Insulin Receptor P2 promoter across the Drosophila phylogeny

“…The identification of the TFBSs contained in cis -regulatory elements constitutes the first step to elucidate the genetic and molecular mechanisms responsible for cis -regulatory divergence among species. We focused on the regulation of the InR gene transcription from its P2 promoter, despite that its transcript yield is much lower than from its P1 promoter, because a significant direct activation of P2 by dFOXO has been confirmed both in vitro and in vivo [ 7 , 16 ] whereas dFOXO also indirectly activates or represses additional enhancers located within introns of InR gene [ 7 ]. Previous band-shift studies had shown that in D .…”

“…Expression from the P1 promoter that drives the highest basal level of InR transcription was initially considered to be stable [ 6 ]. Recent work has, however, revealed that the regulation of InR expression from P1 is actually more complex as it is influenced by four intronic enhancers, with two of them activating transcription in response to dFOXO and the other two repressing it [ 7 ].…”

“…The binding of dFOXO upstream of promoter P2 was partially characterized by band shift analysis, which revealed five 100–150 bp fragments bound by dFOXO spanning a 1.4 kb region. Also occupancy by dFOXO in a 1.5 kb fragment upstream of the P2 promoter has been observed in vivo [ 7 , 16 ]. Each of these fragments contains putative FOXO4 recognition elements.…”

Cucurbita ficifolia Bouché aumenta la secreción de insulina en la línea celular RINm5F a través de la afluencia de calcio proveniente de retículo endoplásmico

“…El gen que codifica para la insulina está localizado en el cromosoma 11p15. importante en la regulación de la transcripción del gen de insulina [43,44].…”