Biology subjects

Kesireddy, D. K.

Publications and source records attributed to Kesireddy, D. K..

4 recordsLinked to original sources

bioRxiv2026

Combinatorial Control of Corticospinal Axon Growth by Retinoic Acid Receptors

Regeneration of central nervous system (CNS) axons depends on Transcription Factors (TFs) that reactivate developmental growth programs, yet most such factors remain unknown. By intersecting developmental chromatin binding with pro-growth gene networks, we identified two retinoic acid receptor transcription factors, RARA and RARG, whose occupancy at growth-associated genes is progressively lost as neurons mature. Restoring both factors together increased neurite outgrowth beyond either alone in two independent systems, the Neuro-2a cell line and primary cortical neurons. In vivo, the same combination drove cross-midline sprouting after pyramidotomy and long-tract regeneration after thoracic spinal cord crush, with concordant recovery of hindlimb gait and grip strength. Interestingly, neither receptor alone was sufficient, hinting at combinatorial regulation. Single-nucleus transcriptomics delineated that only the combination reactivated relevant cytoskeletal and gene-expression programs, while genome-wide binding maps showed that RARA and RARG partition the regulatory landscape, with RARG dominating promoters and RARA occupying distal enhancers, so that neither receptor reconstitutes the developmental growth state alone. Intriguingly, this cooperative requirement was specific to the CNS: in peripheral sensory neurons, RARG alone was sufficient and RARA was dispensable. These data identify RARA and RARG as novel cooperative regulators of regenerative axon growth in mammalian CNS and PNS neurons and potential targets for therapeutic intervention.

neuroscience↗

bioRxiv2025

PATZ1 remodels the nucleosome landscape to promote chromatin accessibility in injured neurons

Adult central nervous system neurons fail to regenerate after injury, in part due to epigenetic constraints that maintain a growth-restrictive chromatin state. We previously showed that the transcription factor PATZ1 reprograms chromatin accessibility in injured corticospinal neurons to promote axon regeneration, but the underlying mechanism remained unclear. Here we use nucleosome-resolution profiling to reveal that PATZ1 induces widespread nucleosome eviction at regeneration-associated gene loci. PATZ1 treatment dramatically reduces both nucleosome occupancy and fuzziness, indicating active chromatin remodeling rather than passive destabilization. This remodeling occurs preferentially at distal regulatory elements, where PATZ1 drives a greater than 3-fold expansion of H3K27ac-marked active enhancers. Nucleosome eviction at these sites precedes enhancer activation, establishing a mechanistic link between chromatin remodeling and transcriptional reprogramming. Our findings demonstrate that targeted nucleosome eviction at enhancers underlies PATZ1-mediated chromatin reorganization, providing mechanistic insight into how epigenetic barriers to CNS regeneration can be overcome.

neuroscience↗

bioRxiv2025

Nuclear Receptor Transcription factors promote axon regeneration in the Adult Corticospinal Tract

Transcription factors are potent levers for neural repair, but which factors govern regenerative capacity in the corticospinal tract remains largely unknown. By intersecting developmental RNA-seq with ATAC-seq footprinting, we identified two nuclear-receptor transcription factors, NR2F1 and NR2F6, neither previously linked to CNS axon growth, whose chromatin occupancy at pro-growth enhancers is progressively lost as neurons mature. Forced expression of either factor significantly increased neurite outgrowth in single-neuron tracing assays, and each drove strong cross-midline sprouting after pyramidotomy and long-tract CST regeneration after complete thoracic crush, with concordant recovery of hip-rise kinematics and grip strength. Parallel multi-omic profiling (CUT&RUN, snRNA-seq and Ribo-seq) of both factors together with NR2F6 Hi-C revealed distinct mechanisms: NR2F1 reactivated chromatin-remodeling and cytoskeletal programs, whereas NR2F6, via a conserved corepressor domain, re-occupied developmental enhancers, reorganized three-dimensional chromatin architecture into new topologically associating domains, and imposed a transient translational down-shift in which growth-relevant modules were selectively preserved through translational buffering. Together, these data identify NR2F nuclear receptors as regulators of corticospinal regeneration, acting through enhancer redeployment, translational reprogramming and three-dimensional genome reorganization.

neuroscience↗

bioRxiv2025

PATZ1 Reinstates a Growth-Permissive Chromatin Landscape in Adult Corticospinal Neurons After Injury

BackgroundThe failure of axon regeneration in the adult central nervous system represents a major barrier to recovery from spinal cord injury and neurodegenerative disease. Pro-growth transcription factors can promote regenerative responses, but their effects remain partial, suggesting that additional restraints must be relieved for these factors to achieve their full potential. The chromatin landscape of adult neurons has emerged as a candidate mechanism, yet we lack a developmental map of when and how this epigenetic restriction occurs, whether injury can reverse it, and how to therapeutically target it. ResultsWe assembled a comprehensive chromatin accessibility atlas spanning mouse forebrain development from embryonic day 11 through adulthood using bulk and single-nucleus ATAC-seq. This revealed progressive restriction of growth-gene promoters and enhancers across postnatal development, leaving over 95% of growth-associated regulatory elements substantially inaccessible in mature neurons. We found that the distance between injury site and neuronal cell body determines the magnitude of chromatin reopening: intracortical lesions proximal to motor cortex soma triggered ten-fold greater enhancer reactivation compared to distal thoracic spinal cord crush. Motif analysis identified PATZ1, a chromatin-remodeling transcription factor, as correlated with this proximity effect. Viral delivery of PATZ1 to adult cortex converted the limited epigenomic response to distal injury into a profile approaching that of proximal injury, selectively reopening enhancers at growth-associated loci and depositing active H3K27ac marks. Hi-C analysis demonstrated that PATZ1 additionally reorganizes higher-order chromatin architecture, inducing compartment switching at growth loci and remodeling topologically associating domain boundaries. Integration with single-nucleus transcriptomics revealed that while PATZ1 selectively opens chromatin at growth genes, transcriptional output and axon regeneration remain modest, indicating that combinatorial approaches pairing epigenetic priming with pro-growth transcription factors may be required for functional repair. ConclusionsThis study provides a developmental timeline of chromatin closure at regeneration-associated genes and identifies PATZ1 as a molecular tool capable of reversing this epigenetic barrier in adult neurons. Our findings indicate that chromatin accessibility functions as a gatekeeping mechanism that must be addressed before transcription factor-based therapies can achieve their full effect, establishing epigenetic priming as a targetable component of CNS repair strategies.

neuroscience↗