Transcription Elongation Factors in Health and Disease

Abstract

Gene expression is a complex process that establishes and maintains a specific cell state. Transcription, an early event during the gene expression, is fine-tuned by a concerted action of a plethora of transcription factors temporally and spatially in response to various stimuli. Most of the earlier research has focused on the initiation of transcription as a key regulatory step. However, work done over the last two decades has highlighted the importance of regulation of transcription elongation by RNA Pol II in the implementation of gene expression programs during development. Moreover, accumulating evidence has suggested that dysregulation of transcription elongation due to dysfunction of transcription factors can result in developmental abnormalities and a broad range of diseases, including cancers. In this chapter, we review recent advances in our understanding of the dynamics of transcription regulation during the elongation stage, the significance of transcriptional regulatory complexes, and their relevance in the development of potential accurate therapeutic targets for different human diseases.

A novel variant in AFF3 underlying isolated syndactyly

“…AFF family proteins form SEC with p-TEFB, ELL, and EAF proteins to enhance the activity of RNA polymerase II and promote transcription elongation. 8 AFF proteins share functional domains including the N-terminal homology domain (NHD), AF4/LAF4/FMR2 homology domain (ALF), and the C-terminal homology domain (CHD) (Figure 1D). 7 The ALF domain promotes protein degradation while CHD is involved in dimerization and localization of the protein into puncta in the nucleus.…”

“…In this study, we identified a novel pathogenic variant (NM_001025108: c.2915G > C: p.Arg972Pro) in AFF3 in a Pakistani family with isolated syndactyly. AFF family proteins form SEC with p‐TEFB, ELL, and EAF proteins to enhance the activity of RNA polymerase II and promote transcription elongation 8 . AFF proteins share functional domains including the N‐terminal homology domain (NHD), AF4/LAF4/FMR2 homology domain (ALF), and the C‐terminal homology domain (CHD) (Figure 1D).…”

“…7 AFF proteins form super elongation complexes (SEC) with other proteins that enhance the activity of RNA polymerase II and promote transcriptional elongation. 8 De novo variants in AFF3 have been linked to KINSSHIP syndrome (MIM619297), a syndrome characterized by horseshoe kidney, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary defects. 9 In this study, we describe a three-generation Pakistani pedigree consisting of isolated syndactyly of 3rd-4th and 4th-5th fingers due to a novel heterozygous pathogenic variant in AFF3 (NM_001025108: c.2915G > C: p.Arg972Pro) located on chromosome 2q11.2.…”

“…AFF3 is a member of the AFF family of nuclear transcription activating factors including AFF1/AF4, AFF2/FMR2, and AFF4/AF5q3 7 . AFF proteins form super elongation complexes (SEC) with other proteins that enhance the activity of RNA polymerase II and promote transcriptional elongation 8 . De novo variants in AFF3 have been linked to KINSSHIP syndrome (MIM619297), a syndrome characterized by horseshoe kidney, mesomelic dysplasia, seizures, hypertrichosis, intellectual disability and pulmonary defects 9 .…”