Endocrine Abstracts (2008) 16 S11.2

Mechanisms of selective gene expression in development

Veronica van Heyningen

MRC Human Genetics Unit, Edinburgh, UK.

The concept of tissue-specific gene expression is familiar to endocrinologists. Starting from the multipotent fertilized egg, selective gene expression is required to generate different tissue and cell types during development. There is generally progressive differentiation of initially dividing, but progressively committed, cells to form mature organs. Timing, size and positioning of organs and the setting up of connections between them all require complex regulation by networks of transcription factors and signaling molecules, which are also involved in controlling the final stages of differentiation. Regulated gene expression is also necessary for continuing finely-tuned differentiated and adult function, for example controlled endocrine activity. Gene expression is regulated at several different levels, some of which are inter-dependent. Firstly, DNA itself can be modified, for example by methylation. Chromatin organization – the compacting of DNA – is effected through differential binding of general and specific proteins. Accessibility of DNA for transcription is controlled, at one level, by secondary modifications (e.g. methylation, acetylation) of chromatin proteins including histones and structural non-histone molecules. Gene expression is modulated by the binding of upstream transcription factors, which may act as repressors or as activators. Often several TFs work together in concert, frequently showing complex auto- and cross-regulation. Their functions are highly dosage sensitive and their exact expression is mediated through the binding of hierarchies of multiple TFs to complex conserved interactive DNA sites, often lying long distances from the transcribed gene. Many developmental anomalies, for example of the pituitary or the pancreas, are caused by TF mutations.

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