Ish Venkatesh

Research Assistant Professor

Marquette University

My research revolves around understanding molecular mechanisms that control axon growth, with the ultimate goal of using this information to induce axon regeneration following injury. I have spent the last decade tackling the problem of why injured neurons in the central nervous system fail to upregulate the right sets of genes supportive of axon re-growth, which ultimately determines regenerative success. I have identified and addressed transcriptional and epigenetic barriers to re-growth using a combination of methods including Bioinformatics, Functional Genomics, and High-Content Screening. I am currently looking to transition to a tenure track position in India in the coming year.

Interests

Axon regeneration
Spinal Cord Injury
Gene regulation
3D Genomics

Education

PhD in Neuroscience, 2014
University of Wisconsin, Milwaukee
Bachelors in Biotechnology, 2009
Anna University

Experience

Research Assistant Professor

Marquette University

Mar 2018 – Present Wisconsin, USA

Post Doc

Marquette University

Sep 2014 – Feb 2018 Wisconsin, USA

Funding

Thanks to my current and previous funding sources!

NSF-XSEDE - Venkatesh (PI)

$200,000 in computational resources Jul 2020 – Jul 2022

Bioinformatic approaches to identify pro-growth gene treatments for Spinal Cord Injury

NIH R21 - R21NS106309 – Venkatesh (Co-I)

$415,000 Sep 2018 – Sep 2020

Regulation of CNS Regeneration by Chromatin Accessibility and Pioneer Factors

Craig H Nielsen post-doctoral fellowship - Venkatesh (PI)

$150,000 Sep 2016 – Sep 2018

Epigenetic manipulation of axon growth in mammalian CNS neurons

NSF-XSEDE - Venkatesh (PI)

$150,000 in computational resources Mar 2016 – Mar 2018

In silico frameworks to identify novel transcription factor combinations that synergize to drive growth in CNS neurons

Projects

Transcriptional barriers to regrowth

Successful axon re-growth and the capacity of an injured neuron to reboot transcriptional growth machinery is closely linked. We have identified two key transcriptional barriers to re-growth (1) Lack of activating transcription factors to reactivate growth networks following injury (2) Presence of repressive transcription factors that prevent reactivation of growth networks following injury. Using a hybrid bioinformatics/functional screening strategy, we continue to make progress in mitigating these barriers.

Epigenetic barriers to axon re-growth

A fundamental barrier to axon re-growth is chromatin accessibility. We and others have shown that as neurons mature, growth-relevant genes shift to a closed conformation limiting transcription factor binding and re-growth response. Reversing this epigenetic constraint is key to full efficacy of gene treatments. Using bioinformatics modeling, we have identified a targeted set of chromatin modifiers predicted to revert accessibility of growth genes to a more open conformation in adult neurons, and are currently screening candidates in functional assays.

Open-access regulatory genomics database

Mammalian CNS neurons aren’t always refractory to re-growth, instead lose the ability in a discrete developmental transition. Identifying the molecular regulatory codes that control this developmental transition is the first-step in devising strategies to reprogram adult neurons back to a growth-competent state. Projects like the ENCODE consortia have generated several brain-specific genomics datasets that comprehensively profile various molecular changes across neuronal maturation. Yet, accessing, integrating and visualizing these datasets require computational expertise. We have developed an open-access, interactive website that allows users to probe temporal patterns of gene expression, chromatin accessibility, functional enhancers and transcription factor binding across mouse forebrain development accessible at mousebraindev.com

3D genome topology in the context of axon regeneration

Transcription factor activity is intricately linked to the three-dimensional organization of the genome. Transcription factors can directly bind to promoters to activate gene expression. However, the maximal transcriptional output is achieved when TFs bind distal regulatory regions called enhancers, and 3D looping of DNA brings an enhancer into physical proximity with a promoter. In recent years, several studies have documented the importance of optimal 3D genome architecture in regulating multiple biological processes from stem cell biology, cell differentiation, organ development, etc via modulation of TF activity. We have isolated regulatory elements that maintain optimal 3D genome architecture supportive of developmental axon growth and are currently investigating the influence of 3D genome topology in the context of regeneration.

DNA repair and axon growth

Recently we have shown that forced overexpression of two transcription factors KLF6/Nr5a2 leads to the upregulation of genes involved in DNA repair. DNA damage is a frequent consequence of increased cellular metabolism, such as transcription in many dividing cells including neuronal progenitor cells. During development, DNA repair mechanisms are active in progenitor cells, allowing repair to proceed alongside active transcription, preserving genome integrity, and promoting effective axon growth. Using bioinformatics approaches, we have identified that several pro-growth TFs occupy DNA repair genes during developmental axon growth. We are now exploring the link between DNA repair and axon growth in CNS neurons.

Recent Talks

Computational approaches identify novel transcription factor combinations that promote corticospinal axon growth after injury

Jun 26, 2020

Preprints

Ishwariya Venkatesh, Vatsal Mehra, Zimei Wang, Matthew T Simpson, Erik Eastwood, Advaita Chakraborty, Zac Beine, Derek Gross, Michael Cabahug, Greta Olson, Murray G Blackmore

June 2020 Nature Communications

Co-occupancy analysis reveals novel transcriptional synergies for axon growth

Transcription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to injury or disease. Because TFs often depend on cooperative activity, a major challenge is to identify and deploy optimal sets. Here we developed a novel bioinformatics pipeline, centered on TF co-occupancy of regulatory DNA, and used it to predict factors that improve axon growth in corticospinal tract (CST) axons when combined with a known pro-regenerative TF, Klf6. Assays of neurite outgrowth confirmed cooperative activity by 12 candidates, and in vivo testing showed strong promotion of CST growth upon combined expression of Klf6 and Nr5a2. Transcriptional profiling of CST neurons identified Klf6/Nr5a2-responsive gene networks involved in macromolecule biosynthesis and DNA repair. These data identify novel TF combinations that promote enhanced CST growth, clarify the transcriptional correlates, and provide a bioinformatics roadmap to detect TF synergy. ### Competing Interest Statement The authors have declared no competing interest.

Publications

Quickly discover relevant content by filtering publications.

Co-occupancy analysis reveals novel transcriptional synergies for axon growth

Transcription factors (TFs) act as powerful levers to regulate neural physiology and can be targeted to improve cellular responses to …

Ishwariya Venkatesh, Vatsal Mehra, Zimei Wang, Matthew T Simpson, Erik Eastwood, Advaita Chakraborty, Zac Beine, Derek Gross, Michael Cabahug, Greta Olson, Murray G Blackmore

KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons

The failure of axon regeneration in the CNS limits recovery from damage and disease. Members of the KLF family of transcription factors …

Zimei Wang, Vatsal Mehra, Matthew T Simpson, Brian Maunze, Advaita Chakraborty, Lyndsey Holan, Erik Eastwood, Murray G Blackmore, Ishwariya Venkatesh

Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons

Axon regeneration in the central nervous system is prevented in part by a developmental decline in the intrinsic regenerative ability …

Ishwariya Venkatesh, Vatsal Mehra, Zimei Wang, Ben Califf, Murray G Blackmore

Ish Venkatesh

Research Assistant Professor

Marquette University

Interests

Education

Experience

Research Assistant Professor

Marquette University

Post Doc

Marquette University

Funding

NSF-XSEDE - Venkatesh (PI)

NIH R21 - R21NS106309 – Venkatesh (Co-I)

Craig H Nielsen post-doctoral fellowship - Venkatesh (PI)

NSF-XSEDE - Venkatesh (PI)

Projects

Transcriptional barriers to regrowth

Epigenetic barriers to axon re-growth

Open-access regulatory genomics database

3D genome topology in the context of axon regeneration

DNA repair and axon growth

Recent Talks

Computational approaches identify novel transcription factor combinations that promote corticospinal axon growth after injury

Preprints

Co-occupancy analysis reveals novel transcriptional synergies for axon growth

Publications

Co-occupancy analysis reveals novel transcriptional synergies for axon growth

KLF6 and STAT3 co-occupy regulatory DNA and functionally synergize to promote axon growth in CNS neurons

Developmental chromatin restriction of pro-growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons

Selecting optimal combinations of transcription factors to promote axon regeneration: Why mechanisms matter

Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo

MASH1/Ascl1a Leads to GAP43 Expression and Axon Regeneration in the Adult CNS

The tumor suppressor HHEX inhibits axon growth when prematurely expressed in developing central nervous system neurons