Biology subjects

Hobbs, J. W.

Publications and source records attributed to Hobbs, J. W..

4 recordsLinked to original sources

bioRxiv2026

Transitory enhancement of GATA2 chromatin engagement during early erythroid differentiation

Erythroid differentiation requires precise regulation of transcription factor binding to chromatin targets as hematopoietic progenitors relinquish multipotency and activate lineage programs. GATA2 maintains progenitor identity and is thought to be progressively silenced as GATA1 levels rise; however, the precise changes in GATA2 chromatin binding kinetics during this transition remain undefined. Here, we combined live-cell single-molecule imaging in cell lines and primary mouse progenitors with CUT&Tag chromatin profiling to define GATA2 activity during erythropoiesis. Single-molecule tracking resolved two interaction modes: short-lived (<1 s) searching interactions and long-lived (>5 s) binding. Surprisingly, early erythroid differentiation was characterized by a transitory strengthening of long-lived GATA2 chromatin engagement. This manifested as increased residence time of GATA2 bound to chromatin in G1E-ER4 cells and an expansion of the long-lived bound population in HPC7 cells and primary mouse progenitors. This transitory phase of enhanced engagement declined upon further differentiation. Genome-wide mapping identified regulatory elements selectively occupied by GATA2 during this early transition state, revealing promoter-proximal sites enriched for GATA/RUNX motifs and distal elements containing composite GATA/E-box signatures. Together, our imaging and chromatin profiling indicate that GATA2 chromatin engagement is kinetically remodeled at the onset of differentiation, with early recruitment targets partitioning into distinct promoter- and enhancer-associated subclasses. These results support a model in which transcription factor kinetics constitute a dynamic chromatin engagement layer that characterizes the GATA2-to-GATA1 transition.

cell biology↗

bioRxiv2024

D-type cyclins regulate DNA mismatch repair in the G1 and S phases of the cell cycle, maintaining genome stability

The large majority of oxidative DNA lesions occurring in the G1 phase of the cell cycle are repaired by base excision repair (BER) rather than mismatch repair (MMR) to avoid long resections that can lead to genomic instability and cell death. However, the molecular mechanisms dictating pathway choice between MMR and BER have remained unknown. Here, we show that, during G1, D-type cyclins are recruited to sites of oxidative DNA damage in a PCNA- and p21-dependent manner. D-type cyclins shield p21 from its two ubiquitin ligases CRL1SKP2 and CRL4CDT2 in a CDK4/6-independent manner. In turn, p21 competes through its PCNA-interacting protein degron with MMR components for their binding to PCNA. This inhibits MMR while not affecting BER. At the G1/S transition, the CRL4AMBRA1-dependent degradation of D-type cyclins renders p21 susceptible to proteolysis. These timely degradation events allow the proper binding of MMR proteins to PCNA, enabling the repair of DNA replication errors. Persistent expression of cyclin D1 during S-phase increases the mutational burden and promotes microsatellite instability. Thus, the expression of D-type cyclins inhibits MMR in G1, whereas their degradation is necessary for proper MMR function in S. One-Sentence SummaryTo maintain genome stability, D-type cyclins limit mismatch repair (MMR) in G1, whereas their degradation is necessary for proper MMR function in S phase.

cell biology↗

bioRxiv2021

Induction of Bdnf from promoter I following electroconvulsive seizures contributes to structural plasticity in neurons of the piriform cortex

The efficacy of electroconvulsive therapy (ECT) as a treatment for psychiatric disorders, including major depressive disorder (MDD) is hypothesized to depend on induction of molecular and cellular events that trigger structural plasticity in neurons. Electroconvulsive seizures (ECS) in animal models can help to inform our understanding of how electroconvulsive therapy (ECT) impacts the brain. ECS induces structural plasticity in neuronal dendrites in many brain regions, including the piriform cortex, a highly epileptogenic region that has also been implicated in depression. ECS-induced structural plasticity is associated with differential expression of unique isoforms encoding the neurotrophin, brain-derived neurotrophic factor (BDNF), but the functional significance of these transcripts in dendritic plasticity is not clear. Here, we demonstrate that different Bdnf isoforms are expressed non-stochastically across neurons of the piriform cortex following ECS. Specifically, cells expressing Bdnf exon 1-containing transcripts show a unique spatial recruitment pattern in response to ECS. We further demonstrate that Bdnf Ex1 expression in these cells is necessary for ECS-induced dendritic spine plasticity.

neuroscience↗

bioRxiv2018

BDNF-TrkB signaling in oxytocin neurons contributes to maternal behavior

Brain-derived neurotrophic factor (Bdnf) transcription is controlled by several promoters, which drive expression of multiple transcripts encoding an identical protein. We previously reported that BDNF derived from promoters I and II is highly expressed in hypothalamus and is critical for regulating aggression in male mice. Here we report that BDNF loss from these promoters causes reduced sexual receptivity and impaired maternal care in female mice, which is concomitant with decreased oxytocin (Oxt) expression during development. We identify a novel link between BDNF signaling, oxytocin, and maternal behavior by demonstrating that ablation of TrkB selectively in OXT neurons partially recapitulates maternal care impairments observed in BDNF-deficient females. Using translating ribosome affinity purification and RNA-sequencing we define a molecular profile for OXT neurons and delineate how BDNF signaling impacts gene pathways critical for structural and functional plasticity. Our findings highlight BDNF as a modulator of sexually-dimorphic hypothalamic circuits that govern female-typical behaviors.

neuroscience↗