Abstract
The bHLH proteins are a family of eukaryotic transcription factors regulating expression of a wide range of genes involved in cell differentiation and development. They contain the Helix-Loop-Helix (HLH) domain, preceded by a stretch of basic residues, which are responsible for dimerization and binding to E-box sequences. In addition to the well-preserved DNA-binding bHLH domain, these proteins may contain various additional domains determining the specificity of performed transcriptional regulation. According to this, the family has been divided into distinct classes. Our aim was to emphasize the significance of existing disordered regions within the bHLH transcription factors for their functionality. Flexible, intrinsically disordered regions containing various motives and specific sequences allow for multiple interactions with transcription co-regulators. Also, based on in silico analysis and previous studies, we hypothesize that the bHLH proteins have a general ability to undergo spontaneous phase separation, forming or participating into liquid condensates which constitute functional centers involved in transcription regulation. We shortly introduce recent findings on the crucial role of the thermodynamically liquid-liquid driven phase separation in transcription regulation by disordered regions of regulatory proteins. We believe that further experimental studies should be performed in this field for better understanding of the mechanism of gene expression regulation (among others regarding oncogenes) by important and linked to many diseases the bHLH transcription factors.
Highlights
The bHLH proteins are the important family of transcription factors (TFs) present in all eukaryotes: from yeasts [1,2] and fungi [3] to plants [4] and metazoans [5,6,7,8,9,10]
Phosphorylation change the interaction pattern allowing C-terminal domain (CTD) to engage in new multivalent interactions with selected partners [139]. These results indicate that liquid-liquid phase separation (LLPS) allows for the condensation of cofactors, that in turn triggers posttranslational modifications leading to the reorganization of the condensate components
As we got positive results for the previously performed prediction of disorder, which was shown to be important for LLPS initiation [76,121,122], we decided to perform in silico analyses to predict if members of the bHLH family comprise putative sequences able to create liquid condensates
Summary
The bHLH (basic Helix-Loop-Helix) proteins are the important family of transcription factors (TFs) present in all eukaryotes: from yeasts [1,2] and fungi [3] to plants [4] and metazoans [5,6,7,8,9,10]. Negative transcription regulators interacting with corepressors (Groucho); neurogenesis, vasculogenesis, mesoderm segmentation, myogenesis, T lymphocyte development, cardiovascular development and homeostasis; effectors of Notch signalling [28]; in Drosophila: regulation of differentiation, anteroposterior segmentation and sex determination transcription regulation in response to physiological and environmental signals: xenobiotics, hypoxia, development, circadian rhytms general partners for subclass I bHLH-PAS proteins. Both class I (known as E proteins) and class II of the bHLH TFs do not possess domains additional to the bHLH. The members of subclass II of bHLH-PAS TFs -ARNT proteins are general dimerization partners of the subclass I members
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