Research interests:

How have recent genomic changes contributed to the evolution of human gene-regulatory networks?

This is the main research interest in my group. In particular, how has the evolution of the human genome shaped gene regulatory networks involved in human embryonic brain development.

Genomic changes can be small, such as retrotransposon insertions, or big, such as segmental duplications of whole segments of the genome. Genomic modifications happened frequently during primate evolution, but the extent to which individual evolutionary genomic events accounted for changes in gene expression and contributed to the evolution of species remains unclear.  

In previous work (Jacobs et al., 2014; Nature) we show how KRAB zinc finger genes in our genome are in a continuous battle against retrotransposon invasions, revealing how our genome is actually in a war against itself.

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13760.html

As a result of this evolutionary armsrace, both retrotransposons and KRAB zinc finger genes become heavily integrated in pre-existing gene regulation pathways which adds an extra level of complexity to how, where and when genes in our genome are shut on or off.

My group currently investigates how this extra layer of retrotransposon-mediated gene control has led to a re-shaping of gene regulatory networks involved in human brain development. My research aims to pinpoint how specific genomic changes may have contributed to the evolutionary increase in size and complexity of the human neocortex and understand how these changes may relate to human's increased susceptibility to neurological diseases such as Autism and Schizophrenia.

5 week old human 'minibrain' in a dish, with radially organized PAX6 positive (green) neural stem cells and TBR1-positive (red) cortical neurons

To study primate genome evolution in the context of brain development, we are using human and primate stem cell lines as a source for cortical neurons. Upon culturing of these cells in specialized medium and subjecting them to multiple developmental signals, these cells can be directed into highly organized cortical tissues. We call these tissues 'cortical organoids' or 'minibrains' and showed that they recapitulate key aspects of human brain development as observed during early stages of embryonic development. The opportunity to generate cortical tissues that mimic early developmental stages of brain development, allows us to investigate the functionality of genomic novelties in the context of the development and evolution of the primate and human neocortex.

The Jacobs Lab; always a lot of fun...

Research Line 1:

Impact of new retrotransposon insertions on the evolution of primate neural gene regulatory pathways

Retrotransposons are virus-derived mobile DNA elements that retained the capability to copy-paste themselves in the host genome, long after the initial attack of the virus and the insertion of the viral DNA into our genome. As a result, over 50% of the human genome is retrotransposon-derived, showing that mobile DNA elements have accumulated in our genome over the course of mammalian evolution.

Some recently emerged retrotransposon-families, such as LINE1 and SVA elements are still active in our genome and while new insertions can give rise to disease, they are an important source for genomic variability responsible for the continuing evolution of our genome. Even compared between the human and chimpanzee genomes, many thousands of lineage-specific retrotransposon insertions exist.  The viral-like gene-regulatory properties of retrotransposons can have significant effects on gene expression when insertions of these ‘mobile promoters’ or ‘mobile enhancers’ happen near genes.

In previous work (Jacobs et al., 2014; Nature;  http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13760.html) we have found that two primate-specific KRAB zinc finger gene have recently evolved to repress the activity of SVA and L1PA retrotransposons. This study shows how our genome is in a continuous battle against retrotransposon invasions and explains the rapid expansion of KRAB zinc finger genes in primate genomes. Intriguingly, the genome’s effort to silence retrotransposons also affects genes in the direct neighborhood of their insertion sites, suggesting that both retrotransposons and KRAB zinc finger genes become integrated in pre-existing gene regulation pathways and may therefore be an important source for the evolution of gene-regulatory novelties.

http://phenomena.nationalgeographic.com/2014/09/28/the-human-genome-is-in-stalemate-in-the-war-against-itself/ 

Currently, my group investigates the extent to which human-lineage specific retrotransposon insertions and the KRAB zinc fingers that evolved to repress them have contributed to the evolution of neural gene-regulatory pathways and how these new regulatory properties relate to human neurological disease.

Research Line 2:

The role of new genes formed by segmental duplications in human brain development

The Neocortex has undergone a dramatic expansion during primate evolution. Previous work (Jacobs et al., submitted) at the University of California, Santa Cruz, aimed at characterizing gene-regulatory networks that drive the earliest stages of cortical development and comparing cross species to identify aspects that are unique to humans. This analysis revealed the existence of a set of new highly expressed neurodevelopmental genes in humans, that have formed by segmental duplication events after divergence of macaque monkeys from the ape-human ancestor.

This gene-family is not alone. Many other multi-copy genes exist in our genome, some of which we know are highly expressed during early developmental stages of human cerebral organoid development. Since very recent gene-duplications result in two nearly identical and therefore nearly indistinguishable paralogous genes on the genome, most of these duplicated genes have escaped the attention.

It is becoming increasingly clear that big chromosomal rearrangements such as gene duplications may have had a significant impact on the evolution of species. Current research in my group focusses on neurally expressed multi-copy genes and the impact of gene duplication events on the evolution of human neural gene-regulatory pathways.

Generation of human brain tissue in a dish

Human ESC-derived Cerebral Organoid, showing the radially organized distribution of PAX6 positive neural stem cells and TBR1-positive cortical neurons

F.M.J. Jacobs, D. Greenberg, N. Nguyen, M. Haeussler, A. Ewing, S. Katzman, B. Paten, S.R. Salama, D. Haussler. An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature, 516, 242–245  (11 December 2014)

C.S. Onodera, J.G. Underwood, S. Katzman, F.M.J. Jacobs, D. Greenberg, S.R. Salama, D. Haussler (2012). Gene isoform specificity through enhancer-associated antisense transcription. PLoS One, 2012;7(8):e43511

F.M.J. Jacobs, J.V. Veenvliet, W.H. Almirza, E. Hoekstra, L. von Oerthel, A.J.A. van der Linden, R. Neijts, M. Groot Koerkamp, D. van Leenen, F. Holstege, J.P.H. Burbach, M.P. Smidt. (2011). Retinoic acid-dependent and -independent gene-regulatory pathways of Pitx3 in meso-diencephalic dopaminergic neurons. Development, Dec;138(23):5213-5222

F.M.J. Jacobs, A.J.A. van der Linden, Y. Wang, L. von Oerthel, H.S. Sul, J.P.H. Burbach, M.P. Smidt. (2009). Identification of Dlk1, Ptpru and Klhl1 as novel target genes of Nurr1 in meso-diencephalic dopamine neurons. Development, Jul; 136(14): 2363-2373

F.M.J. Jacobs, S. van Erp, A.J.A. van der Linden, L. von Oerthel, J.P.H. Burbach, M.P. Smidt (2009). Pitx3 potentiates Nurr1 in dopamine neuron terminal differentiation through release of SMRT-mediated repression. Development, Feb; 136(4): 531-540

F.M.J. Jacobs, S.M. Smits, C.W. Noorlander, L. von Oerthel, A.J.A. van der Linden, J.P.H. Burbach, M.P. Smidt (2007). Retinoic acid counteracts developmental defects in the substantia nigra caused by Pitx3-deficiency. Development, Jul; 134(14): 2673-84

F.M.J. Jacobs, S.M. Smits, K.J. Hornman, J.P.H. Burbach, M.P. Smidt (2006). Strategies to unravel molecular codes essential for the development of meso-diencephalic dopaminergic neurons. Journal of Physiology, Sep 1;575(Pt 2): 397-402

M.F.M. Hoekman, F.M.J. Jacobs, M.P. Smidt, J.P.H. Burbach (2006). Spatial and temporal expression of FoxO transcription factors in developing and adult murine brain. Gene Expression Patterns, Jan;6(2): 134-40

L.P. van der Heide, F.M.J. Jacobs, J.P.H. Burbach, M.F.M. Hoekman, M.P. Smidt (2005). FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling.  Biochemical Journal, Nov 1;391(Pt 3): 623-9

F.M.J. Jacobs, L.P. van der Heide, P.J.E.C. Wijchers, J.P.H. Burbach, M.F.M. Hoekman, M.P. Smidt (2003). FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. Journal of Biological Chemistry, 278: 35959-35967

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