Folkert van Werven

 

Regulation of gene expression by transcription of long non-coding RNAs

In eukaryotes including human cells a large fraction of the genome is transcribed into long non-coding RNAs (lncRNAs) with some studies claiming that there are up to two times more lncRNAs than coding transcripts (1-3). Yet, the function of the majority of these transcripts is unknown. Many of the lncRNAs are not well conserved, weakly expressed, and have a short half-life. A common mechanism of action of lncRNAs is the use of transcription coupled chromatin changes that are critical for regulating local gene expression (4). A large part of my laboratory focusses on identifying the functions and mechanisms of these cis-acting lncRNAs. The budding yeast is an ideal model for studying the role of lncRNAs in regulation of gene expression because there is substantial expression of lncRNAs including antisense, intergenic and translationally inert mRNA isoforms (3).

Previous work revealed that entry into meiosis in yeast is repressed by transcription of lncRNAs (4). The work demonstrated that transcription through the promoter recruits histone methyltransferase and the histone deacetylase complexes to establish repressive chromatin that inhibits expression the master regulator of entry into meiosis. Recently, my laboratory identified two different examples of lncRNAs controlling local gene expression. We show that expression of a translationally inert 5' extended mRNA isoform can cause transcriptional interference at a downstream promoter. Furthermore, we have evidence that transcription of multiple lncRNAs can act in a feedback loop and promote a critical cell fate decision yeast. Thus the spectrum of regulation of gene expression by lncRNAs may be much broader than anticipated.

For future work, we would like to address the following questions:

(1) What are the mechanisms by which transcription of lncRNAs controls gene expression?

(2) What are the biological function of these transcripts, particular in cell fate decision making?

(3) How many and which coding genes are regulated by transcription of lncRNAs?

The PhD candidate will work on one of these topics, but the exact project will be determined once he or she joins the lab.

1. Iyer, M. K., Niknafs, Y. S., Malik, R., Singhal, U., Sahu, A., Hosono, Y., Barrette, T. R., Prensner, J. R., Evans, J. R., Zhao, S., Poliakov, A., Cao, X., Dhanasekaran, S. M., Wu, Y.-M., Robinson, D. R., Beer, D. G., Feng, F. Y., Iyer, H. K. and Chinnaiyan, A. M. (2015)
The landscape of long noncoding RNAs in the human transcriptome.
Nature Genetics  47: 199-208. PubMed abstract

2. Hon, C.-C., Ramilowski, J. A., Harshbarger, J., Bertin, N., Rackham, O. J. L., Gough, J., Denisenko, E., Schmeier, S., Poulsen, T. M., Severin, J., Lizio, M., Kawaji, H., Kasukawa, T., Itoh, M., Burroughs, A. M., Noma, S., Djebali, S., Alam, T., Medvedeva, Y. A., Testa, A. C., Lipovich, L., Yip, C.-W., Abugessaisa, I., Mendez, M., Hasegawa, A., Tang, D., Lassmann, T., Heutink, P., Babina, M., Wells, C. A., Kojima, S., Nakamura, Y., Suzuki, H., Daub, C. O., de Hoon, M. J. L., Arner, E., Hayashizaki, Y., Carninci, P. and Forrest, A. R. R. (2017)
An atlas of human long non-coding RNAs with accurate 5ʹ ends.
Nature 543: 199-204. PubMed abstract

3. Xu, Z., Wei, W., Gagneur, J., Perocchi, F., Clauder-Münster, S., Camblong, J., Guffanti, E., Stutz, F., Huber, W. and Steinmetz, L. M. (2009)
Bidirectional promoters generate pervasive transcription in yeast.
Nature 457: 1033-1037. PubMed abstract

4. van Werven, F. J., Neuert, G., Hendrick, N., Lardenois, A., Buratowski, S., van Oudenaarden, A., Primig, M. and Amon, A. (2012)
Transcription of two long noncoding RNAs mediates mating-type control of gametogenesis in budding yeast.
Cell 150: 1170-1181. PubMed abstract