Mechanisms of gene expression

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Transcriptional regulation is the means whereby cells orchestrate expression of individual genes or group of genes. Recent studies with single cells have shown that, for the most part, transcription is not a continuous activity but it occurs in bursts. The amount of RNA produced for each gene is directly proportional to the amplitude and frequency of such bursts. How these two parameters are controlled is not totally clear, but it appears that DNA sequence information at promoters determine the amplitude, while burst frequencies rely on sequence information at enhancers. Promoters and enhancers are also known as gene regulatory elements. Their primary role is to recruit enzymes (polymerases) and other key proteins (transcription factors, activators and inhibitors) that open up the DNA helix and read the genetic information. Another important feature of promoters and enhancers is that to function properly they must either be in close proximity or in contact with each other. These interactions are not only important for gene expression, but as our laboratoratory and others have shown in the past 5 years, they are key to recombination of genes key for the immune system. This fiscal year, our laboratory has continue exploring how the cell facilitate contacts between regulatory DNA to drive transcription and recombination in lymphocytes. Key publications in this area: 1- Zhang et al. Nature, November 2019 and Ba et al. Nature, July 2020. In these manuscripts we have shown in collaboration with Fred Alt (Harvard) that recombination of antibody genes is driven by nuclear architectural proteins CTCF and cohesin. Their activity ensures that B cells express a broad range of antibody receptors with which pathogens are recognized during infection. 2- Senigl et al. Cell Reports, December 2019. In this manuscript we reported in collaboration with David Schatz (Yale) that nuclear architecture facilitates the mutation of antibody receptor genes. This process ensures that antigens (pathogens) are recognized with exquisite affinity during an infection. 3- Liu et al. Cell Research, April 2020. In this report we characterized the role of a DNA repair protein, known as ERCC6L2, in the resolution of DNA breaks intermediate to antibody gene recombination. 4- Xie et al. Nature Methods, April 2020. This paper reports a new microscopy technique that permits visualization of transcriptionally active domains in the mammalian genome.