Scientist of the month: Rob Klose

July's scientist of the month, Rob Klose, has answered a few questions about his research interests and thoughts on epigenetics for us.

His lab revealed some very exciting insights on variant PRC1 and PRC2, recently published in Cell.

Brief biography

Rob Klose, PhD

Rob Klose completed his PhD at the University of Edinburgh with Prof. Adrian Bird studying DNA methylation. He worked with Prof. Yi Zhang at the University of North Carolina at Chapel Hill on histone lysine demethylases.

In 2008 Rob continued his work as a Wellcome Trust Research Fellow and Principal Investigator at the University of Oxford looking into how epigenetic processes contribute to gene regulation.

Rob was selected as a member of the EMBO young investigator program in 2010, he was awarded the prestigious Lister Institute Research Prize in 2011, and he became a Wellcome Trust Senior Research Fellow in 2013.

Q. Briefly what are your current research interests?

We are focused on understanding the function of a poorly characterized class of vertebrate gene regulatory elements called CpG islands. Despite the fact that we have known about CpG islands for over 30 years and that they are associated with roughly two thirds of human gene promoters, it still remains largely unknown how they contribute to gene regulation.

This lack of understanding is particularly concerning given that alterations in CpG island function are a major feature of cancers.

Towards understanding CpG island function, we and others have recently discovered that a family of Zinc Finger CxxC (ZF-CxxC) domain-containing DNA binding proteins associate specifically with CpG islands and recruit chromatin modifying enzymes to alter the epigenetic environment at gene promoters. We are now focused on exploring the link between CpG islands and chromatin structure to dissect their role in gene regulation.

Q. What is the most exciting recent development in your lab?

In studying CpG island function in mouse embryonic stem cells we recently discovered that a ZF-CxxC domain-containing protein, called KDM2B, physically associates with the polycomb repressive complex 1 (PRC1). PRC1 is a chromatin modifying machine that adds a repressive ubiquityl group to histones and in doing so contributes to the epigenetic repression of gene expression during development.

Our understanding of how polycomb group proteins in mammals recognize target sites has remained largely unknown, but the inclusion of KDM2B in PRC1 suggested that recognition of CpG island elements may underpin this process. In a pair of studies published over the past two years (Farcas A. et al, eLife, 2012 and Blackledge N., Cell, 2014) we have demonstrated that KMD2B directly recruits PRC1 to CpG island target sites shedding light on this previously enigmatic process.

Surprisingly, this work further revealed that KDM2B directed PRC1 targeting and activity drives the recruitment of the second polycomb repressive complex, PRC2, which functions to methylate histone tails. This was unexpected as the prevailing views in the field had alternatively posited that PRC2 dependent methylation was responsible for PRC1 recruitment and function.

Our new discovery strongly suggests that KDM2B mediated targeting and activity of PRC1 at CpG island sites can function to initiate formation of repressive polycomb chromatin domains containing both PRC1 and PRC2.

Importantly, a mouse model ablating KDM2B dependent targeting of PRC1 leads to embryonic lethality and classical polycomb phenotypes, underscoring the importance of CpG island recognition in polycomb group protein function during developmental gene regulation.

Q. What other discoveries and next steps does your research project have in store for us?

We are now very much focused on understanding how the chromatin modifying activities brought to CpG islands by ZF-CxxC domain-containing proteins function together to regulate normal gene expression. Given the fact that CpG islands are associated with two thirds of human gene promoters this could have immensely important implications for how we think about gene expression networks in normal biology and human disease.

Q. Which key epigenetic questions would you like to see answered in the next 5-10 years?

Although not something that we work on directly in the lab, there are now a series of compelling paradigms in mammalian model systems for transgenerational epigenetic persistence of phenotypes. These experimentally tractable systems provide a means to begin understanding and dissecting the molecular mechanisms by which these phenotypes are transmitted.

Discovering the epigenetic 'substance(s)' that underpin these transgenerational effects has been a major challenge and their identification will be transformative for the field. I wait with anticipation to see how these discoveries unfold.

Q. What made you focus on epigenetics research?

I have always been fascinated by the fact that a largely fixed genomic DNA sequence can segregate and regulate gene usage to create the vast array of cell types and functionalities necessary for multi-cellular development.

While at the DNA level it is clear that genetic networks are primarily achieved by the activity of transcription factors at specific regulatory DNA sequences, genetic analysis in animal models has revealed an absolute requirement for chromatin based and epigenetic mechanisms in achieving normal gene expression outcomes during development. This implies that how the cell packages and modifies its DNA plays a central role in orchestrating the delicate gene regulatory balance that underpins normal development.

The desire to understand how this fascinating additional layer of gene regulatory capacity works has driven me over my career to focus on dissecting how chromatin biology and epigenetics processes contribute to gene regulation.

Understanding the functionality of these systems is particularly important now that it is becoming clear that chromatin and epigenetic modifiers are central targets in a vast array of human diseases including cancer.

Q. Any words of wisdom for young researchers just starting in epigenetics?

Never accept the prevailing views as dogma, but instead decide for yourself how well experimental observations support them. Our understanding of epigenetic processes in many cases is still rudimentary and therefore our models should be considered evolving and as such must be met with a healthy degree of skepticism in order to support effective testing of their validity.

Q. One thing that you could not live without? (inside or outside the lab)

The love and support of my wife and two boys, they constantly remind me to think of the big picture.