Basic Helix-Loop-Helix (bHLH) Transcription Factors Proteins

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Basic Helix-Loop-Helix (bHLH) Transcription Factors Proteins

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Basic Helix-Loop-Helix (bHLH) Transcription Factors Proteins Background

One group of transcription factors present within all eukaryotic organisms is that of the basic helix-loop-helix (bHLH) family of proteins. The bHLH proteins utilize their helix-loop-helix domains to form homo- or heterodimers with other family members. Once two bHLH proteins have interlocked, they then go on to bind DNA target sequences using their basic domains. bHLH proteins are known to interact with two types of consensus DNA binding sequences: the “E-box” defined as CANNTG, and the “N-box” defined as CACNAG. The bHLH proteins play important roles in the control of cell proliferation, determination and tissue differentiation during the development of animals and plants. In vertebrates, disruption of E-box sites can lead to defects in gene expression in pancreas, neuronal, and muscle cells. The proper regulation and expression of bHLH proteins is required for a large number of developmental processes including B- and Tlymphocyte development, muscle formation, neuronal specification, Drosophila sex determination, and mammalian heart and pancreatic development. The bHLH motif was first identified by Murre et al., in two murine transcription factors El2 and E47. The bHLH domain is approximately 60 amino acids in length and comprises a DNA- binding basic region of 15 amino acids followed by two α-helices separated by a variable loop region. Besides binding to DNA, the bHLH domain also promotes dimerization, allowing the formation of homodimer or heterodimer complexes.
Several bHLH genes have been identified in various organisms whose genome sequences are available. These include eight bHLH genes in yeast, 39 in Caenorhabditis elegans, 39 in Gallus gallus, 39 in Brachydanio rerio, 46 in Ciona intestinalis, 47 in Xenopus laevis, 59 in D. melanogaster, 50 in T. castaneum, 87 in Lagocephalus lagocephalus, 102 in Mus musculus, 118 in Homo sapiens, 167 in Oryza sativa and 147 in Arabidopsis. Recently, in the silk worm, Bombyx mori, 52 bHLH genes have been identified.

The classification of bHLH proteins
The basic helix-loop-helix protein family is divided up into groups according to their additional non-HLH domains, expression patterns, and transcriptional function. Class I bHLH proteins include the vertebrate E2A proteins; E12 and E47, E2-2 and HEB as well as the invertebrate Daughterless (Da) protein. These proteins are usually ubiquitously expressed, are able to homo- or heterodimerize with other classes of bHLH proteins. Class I bHLH proteins function to promote transcription, and are characterized by their AD1 and AD2 transcriptional activation domains. Class II consists of proteins such as Drosophila Twist (Twi), Achaetae (Ac), Scute (Sc), and vertebrate NeuroD, MyoD, MATH, and MASH proteins. 
Class II proteins are expressed in a tissue and cell specific manner and unlike Class I, do not homodimerize. Rather, Class II proteins are known to associate with Class I proteins. Class III bHLH proteins contain a leucine zipper domain and include Myc, TFE3, and SREBP1. Some bHLH proteins considered to be in Class IV bHLH proteins are vertebrate Mad, Max, Mxi1 and Drosophila Mnt, and Max. These proteins are able to heterodimerize with each other or with Myc. The Class VI transcriptional repressors include Drosophila Hairy, Enhancer of split (E[spl]), and vertebrate HES proteins. These proteins are known to act as repressors and have the ability to bind Groucho (Gro). Class VII bHLH proteins are PAS domain proteins such as Sim, Trh, and AHR. All of these classes of bHLH transcription factor proteins contain basic domains used to interact with DNA. 
However, the Class V bHLH proteins lack this domain, which alters their main molecular function. Class V bHLH proteins are unlike any other family member proteins in that they lack a basic domain, or any other domain known to interact with DNA. This class includes the vertebrate Inhibitor of Differentiation 1-4 (Id1-4) and the invertebrate Extramacrochaetae (Emc). This class of bHLH proteins is intriguing because they influence biological processes through an indirect form of regulation known as sequestration. The four Inhibitor of Differentiation proteins have been studied in zebrafish, mice, and human models. These proteins have been identified as potential targets for cancer therapy or prevention. Unfortunately, the four Id proteins are functionally redundant, which can obscure experimental interpretation. A better understanding of what roles these proteins play throughout vertebrate development and in cancerous situations is needed to determine whether Id proteins should be further investigated for promoting anticancer properties.

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