Understanding how a multiple cellular organism arises from a single cell is a major challenge in biology. Each cell fate or cell differentiation programme is controlled by multiple regulatory signals that drive changes in gene expression. Dissecting the mechanisms of gene regulation is key to the understanding of development, but also to diseases such as cancer. As such, how gene expression is regulated during cell differentiation remains poorly understood.

The van Werven lab uses budding yeast gametogenesis  (as known as sporulation) and mamalian neuronal differentiation  as a basic models for deciphering principles of regulating gene expression in general and during cell fate changes. The research can be summarised by two key questions:  How do noncoding RNAs, alternative mRNA isoforms control gene expression? How does a highly conserved RNA modification, N6-methyladenosine (m6A), and its macheninery regulate gene expression?

How does transcript heterogeneity shape gene expression and cell fate?

Changes in 5’end length of messenger RNAs can affect the rate of translation and lead to new protein isoforms . The formation of alternative mRNA isoforms is regulated, at least is part, by alternative transcription start sites (TSS) selection. The regulated usage of alternative TSSs has an important function in controlling gene expression. Transcription from alternative TSSs can influence expression from the main TSS. Studies from my laboratory and others have illustrated that transcription of long upstream mRNA isoforms and long noncoding RNAs direct transcription coupled chromatin changes in cis, which in turn affect transcription from the main TSS. We propose that a primary function for alternative TSSs is to regulate and tune the expression of the main TSS often through transcription coupled chromatin changes. A long term aim of my laboratory is to identify the regulatory principles required for regulation of gene expression via alternative TSSs. The results from these studies will reveal how alternative TSSs shape gene expression and how this controls cell state changes in yeast and mammalian cells. Our work may provide important new insights into how mis-regulation of alternative TSSs drives the onset of diseases such as cancer or neural developmental disorders, which often display pervasive mis-regulation of alternative promoters.

How does the m6A machinery regulate gene expression and cell fate?

The m6A machinery is conserved from yeast to humans and have been implicated in controlling various developmental programs.  Alteration of m6A levels contributes in cancer pathogenesis and developmentIn budding yeast, the accumulation of m6A starts soon after sporulation induction and peaks during pre-meiotic prophase Deposition of m6A in budding yeast is performed by methyltransferase Ime4 (Inducer of meiosis 4 One m6A reader protein has been identified in budding yeast named Pho92, whose m6A reading domain (YTH) is conserved with the mammalian reader proteins . In yeast, progressing through meiosis is impaired or delayed in cells lacking m6A writer and reader proteins . How the m6A machinery controls gene expression and yeast gametogenesis is not understood. The long-term aim is to decipher the functions and mechanisms by which the m6A machinery controls gene expression. It is our hope that the work in yeast will provide insights onto the function and regulation of m6A in human cells and help understanding how mis-regulation of m6A contributes to the onset of diseases such as cancer. We have defined two key directions to study the mechanisms and functions of the m6A machinery. Dissect the mechanism by which the m6A writer machinery select its targets? Determine how the m6A machinery controls gene expression?