Transcriptional co-activators: emerging roles in signaling pathways and potential therapeutic targets for diseases

Abstract

Specific cell states in metazoans are established by the symphony of gene expression programs that necessitate intricate synergic interactions between transcription factors and the co-activators. Deregulation of these regulatory molecules is associated with cell state transitions, which in turn is accountable for diverse maladies, including developmental disorders, metabolic disorders, and most significantly, cancer. A decade back most transcription factors, the key enablers of disease development, were historically viewed as ‘undruggable’; however, in the intervening years, a wealth of literature validated that they can be targeted indirectly through transcriptional co-activators, their confederates in various physiological and molecular processes. These co-activators, along with transcription factors, have the ability to initiate and modulate transcription of diverse genes necessary for normal physiological functions, whereby, deregulation of such interactions may foster tissue-specific disease phenotype. Hence, it is essential to analyze how these co-activators modulate specific multilateral processes in coordination with other factors. The proposed review attempts to elaborate an in-depth account of the transcription co-activators, their involvement in transcription regulation, and context-specific contributions to pathophysiological conditions. This review also addresses an issue that has not been dealt with in a comprehensive manner and hopes to direct attention towards future research that will encompass patient-friendly therapeutic strategies, where drugs targeting co-activators will have enhanced benefits and reduced side effects. Additional insights into currently available therapeutic interventions and the associated constraints will eventually reveal multitudes of advanced therapeutic targets aiming for disease amelioration and good patient prognosis.

The pharmacoepigenetic paradigm in cancer treatment

“…Histone phosphorylation and ubiquitination are additional modifications with significant roles in gene expression and chromatin dynamics. Phosphorylation, often linked to chromatin condensation, is mediated by specific kinases ( Shi, 2007 ; Rossetto et al, 2012 ), whereas co-activator-mediated ubiquitination is definitively associated with gene activation ( Talukdar and Chatterji, 2023 ). Other modifications, such as glycosylation and sumoylation, although less understood, are recognized for their contribution to chromatin structure and function ( Seeler and Dejean, 2003 ; Ramírez et al, 2009 ).…”