Helix–loop–helix proteins and the advent of cellular diversity: 30 years of discovery

Abstract

Helix-loop-helix (HLH) proteins are dimeric transcription factors that control lineage-and developmental-specific gene programs. Genes encoding for HLH proteins arose in unicellular organisms >600 million years ago and then duplicated and diversified from ancestral genes across the metazoan and plant kingdoms to establish multicellularity. Hundreds of HLH proteins have been identified with diverse functions in a wide variety of cell types. HLH proteins orchestrate lineage specification, commitment, self-renewal, proliferation, differentiation, and homing. HLH proteins also regulate circadian clocks, protect against hypoxic stress, promote antigen receptor locus assembly, and program transdifferentiation. HLH proteins deposit or erase epigenetic marks, activate noncoding transcription, and sequester chromatin remodelers across the chromatin landscape to dictate enhancer-promoter communication and somatic recombination. Here the evolution of HLH genes, the structures of HLH domains, and the elaborate activities of HLH proteins in multicellular life are discussed. Corresponding

Integrated requirement of non-specific and sequence-specific DNA binding in MYC-driven transcription

“…70 amino acids) and is a strict pre-requisite for DNA binding, mediated by the short basic region (15 a.a.) that precedes the HLH (Amati et al, 1992, Blackwood & Eisenman, 1991. In line with those biochemical findings, structural studies on DNA-bound or free dimers, including Myc/Max (Nair & Burley, 2003, Sammak et al, 2019, Max/Max (Brownlie et al, 1997, Ferre-D'Amare et al, 1993, Sauvé et al, 2007, Sauvé et al, 2004 and other bHLH proteins (Murre, 2019), showed that dimerization allows positioning of the basic regions for insertion into the DNA major groove (Fig. EV1A).…”

Mechanical stimulation induced osteogenic differentiation of BMSCs through TWIST/E2A/p21 axis

“…Stem cells and cancer cells share a lot of similarities in gene expression, cellular processes and signal transductions, but there are not many studies researching the effects of HIF-TWIST on normal stem cells. Recent studies have shown that E2A and TWIST both belong to the bHLH protein family [15]. E2A can activate the expression of cyclin-dependent kinases (CDKs) inhibitor p21 gene [16,17]; p21 also plays an important role in the differentiation of osteoblasts and myoblasts [18,19].…”

Comparative Functional Analysis of the Basic Helix-Loop-Helix Proteins in the Clawed Frogs' Genomes With Common Essential Pathways and Enriched Gene Ontology Terms

“…The Basic Helix-Loop-Helix (bHLH) proteins are currently recognized as the most important class of transcription factors. They can form specific interactions with the genetic cis-elements of eukaryotes, thereby activating or inhibiting the transcription and translation of the gene and they may also bind to the DNA binding proteins with activation or inhibition activities (Murre et al, 1989;Murre, 2019). They can combine with other transcription factors to form a complex genetic regulatory network too (Murre et al, 1989;Atchley and Fitch, 1997;Boggon et al, 1999;Luscombe et al, 2000;Riechmann et al, 2000;Stevens et al, 2008;Murre, 2019).…”

“…They can form specific interactions with the genetic cis-elements of eukaryotes, thereby activating or inhibiting the transcription and translation of the gene and they may also bind to the DNA binding proteins with activation or inhibition activities (Murre et al, 1989;Murre, 2019). They can combine with other transcription factors to form a complex genetic regulatory network too (Murre et al, 1989;Atchley and Fitch, 1997;Boggon et al, 1999;Luscombe et al, 2000;Riechmann et al, 2000;Stevens et al, 2008;Murre, 2019). At present, members of the bHLH transcription factor family are found to be crucial and they play many important roles in the cell proliferation and differentiation, body immunity, muscle tissue formation, neurons, resistance to stress, development of the eye and intestine, hematopoietic function and coagulation function, adaptation to hypoxic environment, sex determination and the process of genetic development of animals and plants (Murre et al, 1989;Murre, 2019;Atchley and Fitch, 1997;Boggon et al, 1999;Luscombe et al, 2000: Riechmann et al, 2000Stevens et al, 2008;Wang et al, 2010).…”