Ish Venkatesh

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

Aug 2014 – Dec 2016 Wisconsin, USA

Funding

Thanks to my current and previous funding sources!

NSF-XSEDE - Venkatesh (PI)

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

NIH R21 - R21NS106309 – Venkatesh (Co-I)

Regulation of CNS Regeneration by Chromatin Accessibility and Pioneer Factors

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

Epigenetic manipulation of axon growth in mammalian CNS neurons

NSF-XSEDE - Venkatesh (PI)

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 are currently developing 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.

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.

Publications

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

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

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 …

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 …

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

Recovery from injuries to the central nervous system, including spinal cord injury, is constrained in part by the intrinsically low …

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

o̧pyright 2016 The AuthorsAxon regeneration in adult central nervous system (CNS) is limited in part by a developmental decline in the …

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

Unlike CNS neurons in adult mammals, neurons in fish and embryonic mammals can regenerate their axons after injury. These divergent …

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

o̧pyright 2015 Elsevier Inc.Neurons in the embryonic and peripheral nervous system respond to injury by activating transcriptional …