www.frankjacobslab.com

In the Jacobs Lab we investigate how genomic evolution has shaped and rewired gene regulatory networks involved in human 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. The impact of both types of evolutionary genomic changes on human brain development and disease are the main topics in my lab's research:

Transposable elements and KRAB Zinc fingers; Evolutionary cat and mouse game leading to increased genomic complexity

In previous work (Jacobs et al., 2014; Nature) we showed 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. As a result of this evolutionary armsrace, both retrotransposons and KRAB zinc finger genes become heavily integrated in pre-existing gene regulatory networks, adding an extra level of complexity to how, where and when genes in our genome are shut on or off.

Our lab currently investigates how this extra layer of retrotransposon-mediated gene control has re-shaped gene regulatory networks involved in human brain development. Our research aims to pinpoint how specific classes of transposable elements have contributed to the evolution of human neuronal gene expression networks and understand how these changes may relate to human's increased susceptibility to neurodevelopmental disorders such as Autism and Schizophrenia and human neurodegenerative diseases such as Alzheimer's and Parkinson's disease.

Segmental duplications as source for new human-specific genes

In work that was recently published in 'Cell'  after many years of exciting discoveries, we revealed the existence of a cluster of human-specific genes,  which are highly expressed in neuronal stem cells in the human brain. These human-specific genes were formed by segmental duplications, and their function in neuronal progenitor cells suggest these genes may have contributed to the evolutionary expansion of the human neocortex https://www.cell.com/cell/abstract/S0092-8674(18)30383-0

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.

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.

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.

Evolutionary arms race

In previous work (Jacobs et al., 2014; Nature;  http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13760.html) we 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. Currently, my lab 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 Neocortex has undergone a dramatic expansion during primate evolution. In our lab, we aim to characterize gene-regulatory networks that drive the earliest stages of cortical development with a special focus on aspects unique to humans. In work that was recently published in 'CELL'  after many years of exciting discoveries, we revealed the existence of a cluster of human-specific NOTCH2NL genes,  which are highly expressed in neuronal stem cells in the human brain. These human-specific genes were formed by segmental duplications, and their function in neuronal progenitor cells suggest these genes may have contributed to the evolutionary expansion of the human neocortex (https://www.ncbi.nlm.nih.gov/pubmed/29856954).

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 brain 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.

Ian T. Fiddes, Gerrald A. Lodewijk, Meghan Mooring, Colleen M. Bosworth, Adam D.  Ewing,  Gary L. Mantalas, Adam M. Novak, Anouk van den Bout, Alex Bishara, Jimi L. Rosenkrantz, Ryan Lorig-Roach, Andrew R. Field, Maximilian Haeussler, Lotte Russo, Aparna Bhaduri, Tomasz J. Nowakowski, Alex A. Pollen, Max L. Dougherty, Xander Nuttle, Marie-Claude Addor, Simon Zwolinski, Sol Katzman, Arnold Kriegstein, Evan E. Eichler, Sofie R. Salama, Frank M.J. Jacobs #, David Haussler #. Human-specific NOTCH2NL genes affect Notch signaling and cortical neurogenesis. Cell, 173(6):1356-1369. (2018) (#Shared Last/corresponding authors) 

Michael Coulter, Cristina Dorobantu, Gerrald A. Lodewijk, François Delalande, Sarah Cianferani, Vijay Ganesh, Richard Smith, Elaine Lim, C. Shan Xu, Song Pang, Eric Wong, Hart Lidov, Monica Calicchio, Edward Yang, Dilenny Gonzalez, Thorsten Schlaeger, Ganesh Mochida, Harald Hess, Wei-Chung Allen Lee, Maria Lehtinen, Tomas Kirchhausen, David Haussler, Frank M.J. Jacobs #, Raphael Gaudin #, Christopher A. Walsh #.  The ESCRT-III protein CHMP1A mediates secretion of sonic hedgehog on ART subtype of extracellular vesicles. Cell Reports, 24(4), 973-986 (2018) (#Shared corresponding authors)

Diana Pereira Fernandes, Maina Bitar, Frank M.J. Jacobs#, Guy Barry #.  Long Non-Coding RNAs in Neuronal Aging. Non-Coding RNA (2018), 4(2), 12 (#Shared Last/corresponding authors)

Andrew R. Field, Frank M.J. Jacobs, Ian T. Fiddes, Alex P.R. Phillips, Andrea M. Reyes-Ortiz, Erin LaMontagne, Lila Whitehead, Vincent Meng, Jimi L. Rosenkrantz, Maximillian Haeussler, Sol Katzman, Sofie R. Salama, David Haussler. Structurally conserved primate lncRNAs are transiently expressed during human cortical differentiation and influence cell type specific genes (2018). Under revision; (BioRxiv, https://doi.org/10.1101/232553)

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

Lab Alumni