Receptors Regulating Transcription Factors
A transcription factor (TF) or sequence-specific DNA-binding factor is a protein which controls the rate of transcription of genetic information from DNA to mRNA, by binding to a specific DNA sequence. Their function is to regulate – turn on and off – genes in order to make sure that they are expressed in the right cell at the right time and in the right amount throughout the life of the cell and the organism. Groups of TFs function in a co-ordinated fashion to direct cell division, cell growth and cell death throughout life; cell migration and organisation (body plan) during embryonic development; and intermittently in response to signals from outside the cell, such as hormone. There are up to 2600 TFs in the human genome.
TFs work alone or with other proteins in a complex, by promoting (as an activator) or blocking (as a repressor) the recruitment of RNA polymerase to specific genes. RNA polymerase is the enzyme which performs transcription of genetic information from DNA to RNA.
A defining feature of TFs is that, they contain atleast one DNA-binding domain (DBD), which attaches to a specific sequence of DNA adjacent to the genes which they regulate. TFs are grouped in to classes based on their DBDs. Other proteins like co-activators, chromatin remodelers, histone acetyl transferases, histone deacetylases, kinases and methylases are also essential to gene regulation, but lack DBDs, and hence they are not TFs. TFs are of interest in medicine because TF mutations can cause specific diseases, and medications can be targeted towards them.
TFs are one of the group of proteins which read and interpret the genetic blue print in the DNA. They bind to the DNA and help initiate a programme of increased or decreased gene transcription. They are of vital importance for many important cellular processes. Some of the important functions are listed below:
(i) Basal transcription regulation
An important class of transcription factors is called as general transcription factors (GTFs). Many of these GTFs do not actually bind DNA, but are a part of large transcription pre- initiation complex which interacts with RNA polymerase directly. The pre-initiation complex binds to promoter regions of DNA upstream to the gene that they regulate.
(ii) Differential enhancement of transcription
Other transcription factors differentially regulate the expression of various genes by binding to enhancer regions of DNA adjacent to regulatory genes. These transcription factors are critical to making sure that genes are expressed in the right cell at the right time and in the right amount.
Many transcription factors in multicellular organisms are involved in development. Responding to stimuli, these transcription factors turn on/off the transcription of appropriate genes, which in turn, allows for changes in cell morphology or activities needed for cell fate determination and cellular differentiation; e.g. the Hox transcription factor family is responsible for proper body pattern formation in different organisms.
o Response to intercellular signals
Cells can communicate with each other by releasing molecules which produce signalling cascades within another receptive cell. If the signal requires upregulation or downregulation of genes in the recipient cell, transcription factors will be downstreamed in the signalling cascade; e.g. estrogen signalling of a fairly short signalling cascade involves the estrogen receptor transcription factor.
o Response to environment
Transcription factors can also be downstream of signalling cascades involved in environmental stimuli; e.g. heat shock factor (HSF) upregulates genes necessary for survival at higher temperatures.
o Cell cycle control
Many transcription factors like proto-onco genes or tumour suppressors help regulating the cell cycle. They determine how large a cell will get and when it can divide into daughter cells; e.g. Myc onco gene has important roles in cell growth and apoptosis.
TFs can also be used to alter gene expression in a host cell to promote pathogenesis; e.g. transcription-activator like effectors (TAL effectors) are secreted by Xanthomonas bacteria. When injected into plants, these proteins can alter the nucleus of the plant cell, bind plant promoter sequences, and activate transcription of plant genes that aid in bacterial infection.
TFs are of clinical significance for following two reasons:
• Mutations can be associated with specific diseases
• They can be targets of medications
Following disorders are related to TFs:
• Rett syndrome
• Developmental verbal dyspraxia
• Autoimmune diseases
• Li-Fraumeni syndrome
• Breast cancer
• Multiple cancers
Around 10% of currently prescribed drugs directly target the nuclear receptor class of transcription factors. Tamoxifen for breast cancer and Bicalutamide for prostate cancer are
some of the examples. In addition, various types of anti-inflammatory and anabolic steroids are also from this category. TFs are often indirectly modulated through signalling cascades. TFs outside the nuclear receptor family are more difficult to target with small molecule therapeutics.