Matthew S. Wilken

X-Cell: Scaling Causal Perturbation Prediction Across Diverse Cellular Contexts via Diffusion Language Models

Chloe Wang, Mehran Karimzadeh, Neal G. Ravindra, Lexi R. Bounds et autres

Abstract Causal models of cellular systems hold the promise to empower broad biological discovery, including the systematic identification of novel targets for drug discovery. Predicting how genetic and pathway perturbations reshape gene expression across diverse cellular contexts is a prerequisite for building …

Large-scale discovery of potent, compact and erythroid specific enhancers for gene therapy vectors

Nikoletta Psatha, Pavel Sova, Grigorios Georgolopoulos, Kiriaki Paschoudi et autres

Gene expression during cell development and differentiation is orchestrated by distal regulatory elements that precisely modulate cell selective gene activity. Gene therapy vectors leverage these elements for precise spatiotemporal transgene expression. Here, we develop a one-shot approach to screen candidate regulatory sequences …

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Large-scale discovery of potent, compact and lineage specific enhancers for gene therapy vectors

Nikoletta Psatha, Pavel Sova, Grigorios Georgolopoulos, Kiriaki Paschoudi et autres

Abstract Regulation of gene expression during cell development and differentiation is chiefly orchestrated by distal noncoding regulatory elements that precisely modulate cell selective gene activity. Gene therapy vectors rely on the cellular and context specificity of regulatory DNA elements to express therapeutic …

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Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential

Leah S. VandenBosch, Stefanie G. Wohl, Matthew S. Wilken, Marcus J. Hooper et autres

Diseases and damage to the retina lead to losses in retinal neurons and eventual visual impairment. Although the mammalian retina has no inherent regenerative capabilities, fish have robust regeneration from Müller glia (MG). Recently, we have shown that driving expression of Ascl1 …

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De novo design of protein logic gates

Zibo Chen, Ryan Daniel Kibler, Andrew C. Hunt, Florian Büsch et autres

Designer gates Signaling in cells can occur through protein-protein interactions. Chen et al. describe the design of logic gates that can regulate protein association. The gates were built from small, designed proteins that all have a similar structure but where one module …

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Promoter keyholes enable specific and persistent multi-gene expression programs in primary T cells without genome modification

Matthew S. Wilken, Christie Ciarlo, Jocelynn R. Pearl, Jordan E. Bloom et autres

Non-invasive epigenome editing is a promising strategy for engineering gene expression programs, yet potency, specificity, and persistence remain challenging. Here we show that effective epigenome editing is gated at single-base precision via 'keyhole' sites in endogenous regulatory DNA. Synthetic repressors targeting promoter …

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Quantitative dialing of gene expression via precision targeting of KRAB repressor

Matthew S. Wilken, Christie Ciarlo, Jocelynn R. Pearl, Elaine Schanzer et autres

Abstract Human genes are regulated quantitatively, yet the ability to specify the expression level of a native gene accurately and specifically using a defined reagent has remained elusive. Here we show that precise targeting of KRAB repressive domain within regulatory DNA unlocks …

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STAT Signaling Modifies Ascl1 Chromatin Binding and Limits Neural Regeneration from Muller Glia in Adult Mouse Retina

Nikolas L. Jorstad, Matthew S. Wilken, Levi J. Todd, Connor Finkbeiner et autres

Müller glia (MG) serve as sources for retinal regeneration in non-mammalian vertebrates. We find that this process can be induced in mouse MG, after injury, by transgenic expression of the proneural transcription factor Ascl1 and the HDAC inhibitor TSA. However, new neurons …

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Cis-Regulatory Accessibility Directs Muller Glial Development and Regenerative Capacity

Leah S. VandenBosch, Stefanie G. Wohl, Matthew S. Wilken, Kristin E. Cox et autres

Abstract Diseases and damage to the retina lead to losses in retinal neurons and eventual visual impairment. Although the mammalian retina has no inherent regenerative capabilities, fish have robust regeneration from Müller glia (MG). Recently, we have shown that driving expression of …

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STAT pathway activation limits the Ascl1-mediated chromatin remodeling required for neural regeneration from Müller glia in adult mouse retina

Nikolas L. Jorstad, Matthew S. Wilken, Levi J. Todd, Paul A. Nakamura et autres

Abstract Müller glia can serve as a source for retinal regeneration in some non-mammalian vertebrates. Recently we found that this process can be induced in mouse Müller glia after injury, by combining transgenic expression of the proneural transcription factor Ascl1 and the …

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Open chromatin dynamics in prosensory cells of the embryonic mouse cochlea

Brent A. Wilkerson, Alex Chitsazan, Leah S. VandenBosch, Matthew S. Wilken et autres

Abstract Hearing loss is often due to the absence or the degeneration of hair cells in the cochlea. Understanding the mechanisms regulating the generation of hair cells may therefore lead to better treatments for hearing disorders. To elucidate the transcriptional control mechanisms …

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Genomic analyses of Müller glia identifies additional factors to improve Ascl1-mediated retinal regeneration in mice

Nikolas L. Jorstad, Matthew S. Wilken, Leah S. VandenBosch, Thomas A. Reh

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