Of numbers and movement – understanding transcription factor pathogenesis by advanced microscopy

Disease Models & Mechanisms

Vladana Vukojević¹  Hildegard N. Hall²  Julia M. T. Auer²  Dimitrios K. Papadopoulos²  Kassiani Skouloudaki²  Jack J. Stoddart²  Ana Lima²  Ioannis Christodoulou² 

[1] Center for Molecular Medicine (CMM), Department of Clinical Neuroscience, Karolinska Institutet, 17176 Stockholm, Sweden;MRC Human Genetics Unit, University of Edinburgh, Edinburgh EH4 1XU, UK;

关键词: haploinsufficiency;    quantitative microscopy;    transcription factors;    super-resolution microscopy;    transcriptional regulation;   

DOI  :  10.1242/dmm.046516

来源: DOAJ

【 摘 要 】

Transcription factors (TFs) are life-sustaining and, therefore, the subject of intensive research. By regulating gene expression, TFs control a plethora of developmental and physiological processes, and their abnormal function commonly leads to various developmental defects and diseases in humans. Normal TF function often depends on gene dosage, which can be altered by copy-number variation or loss-of-function mutations. This explains why TF haploinsufficiency (HI) can lead to disease. Since aberrant TF numbers frequently result in pathogenic abnormalities of gene expression, quantitative analyses of TFs are a priority in the field. In vitro single-molecule methodologies have significantly aided the identification of links between TF gene dosage and transcriptional outcomes. Additionally, advances in quantitative microscopy have contributed mechanistic insights into normal and aberrant TF function. However, to understand TF biology, TF-chromatin interactions must be characterised in vivo, in a tissue-specific manner and in the context of both normal and altered TF numbers. Here, we summarise the advanced microscopy methodologies most frequently used to link TF abundance to function and dissect the molecular mechanisms underlying TF HIs. Increased application of advanced single-molecule and super-resolution microscopy modalities will improve our understanding of how TF HIs drive disease.

【 授权许可】

Unknown