Biology subjects

Butz, S.

Publications and source records attributed to Butz, S..

5 recordsLinked to original sources

bioRxiv2026

Syngap1 Synchronizes Relative Neuronal Maturation Across Cortical Areas to Organize Distributed Functional Networks

Neurodevelopmental disorders are increasingly viewed as disorders of distributed brain networks, yet how developmental perturbations generate co-occurring hypo- and hyper-functional network states remains unclear. We show that Syngap1 haploinsufficiency in mice produces opposing cortical activity patterns: sensory-evoked responses exhibit reduced gain, whereas state-linked movement/arousal activity is amplified. Restricting Syngap1 deficiency to developing cortical excitatory neurons reproduces distributed sensory hypofunction but not movement-linked hyperfunction, indicating non-uniform, cell-type-dependent contributions to these patterns. During a postnatal window of circuit assembly, Layer 2/3 intratelencephalic populations across cortical regions occupy distinct maturation states, reflected in separable dendritic architectures and intrinsic excitability. Perturbing Syngap1 reduces this developmental separability through region-dependent, opposite-direction effects on dendritic maturation and inversion of ERK-sensitive control of intrinsic excitability. We propose that coordinated relative maturation of interacting neuronal populations establishes distributed network balance, and that gene-dependent shifts in this coordination produce stable, opposing network states.

neuroscience↗

bioRxiv2024

SETD2 promotes PAF1C interactions with the elongating RNA Pol II and is required for neuronal differentiation

Chromatin modifications are relevant for mammalian development and their aberrant deposition is associated with human disease. While the mechanisms that deposit and remove these modifications have been largely elucidated, their role in regulating gene activity during cellular differentiation have yet to be completely understood. By differentiating a panel of mouse embryonic stem cells lacking major chromatin regulators towards neuronal cells, we identified their requirement at different stages of cellular differentiation. We show that the H3K36me3 methyltransferase SETD2 is important for the establishment of neuronal gene expression during late stages of differentiation, but is dispensable once the cells have fully differentiated. This function is largely independent of the histone methyltransferase activity. By measuring the protein interaction network of elongating RNA Pol II, we identify a novel role for SETD2 in mediating interactions between the PAF1 complex and the elongating RNA Pol II, which is required to ensure optimal transcriptional processivity of neuronal genes.

molecular biology↗

bioRxiv2024

Targeted CRISPR-Cas9 screening identifies transcription factor network controlling murine haemato-endothelial fate commitment

Haematopoiesis is a tightly coordinated process that forms and maintains all blood cells. During development blood generation begins in the yolk sac with the differentiation of haemato-endothelial mesoderm giving rise to haematopoietic progenitors. Which molecular regulators are crucial for haemato-endothelial mesoderm formation remains unclear and has not been studied in an unbiased way. Here we employ a mouse embryonic stem cell model that recapitulates embryonic blood development and perform targeted CRISPR-Cas9 knock out screens focusing on transcription factors and chromatin regulators. Focusing on the transition of primitive towards haematoendothelial mesoderm we identified the known master regulator Etv2 and novel transcription factors including Smad1, Ldb1, Six4 and Zbtb7b acting as crucial drivers or repressors of mesodermal commitment. Our transcriptome analysis highlights that each factor has a precise impact on the gene expression signature of the developing mesoderm resulting in the formation of mesodermal subsets with a defined lineage differentiation bias. Our study reveals novel molecular pathways governing mesodermal development crucial to allow endothelial and haematopoietic lineage specification.

developmental biology↗

bioRxiv2019

TIP5 safeguards genome architecture of ground-state pluripotent stem cells

Chromosomes have an intrinsic tendency to segregate into compartments, forming long-distance contacts between loci of similar chromatin states. However, how genome compartmentalization is regulated remains elusive. We analyzed two closely and developmentally related pluripotent cell types: ground-state ESCs that have an open and active chromatin and developmentally advanced ESCs that display a more closed and repressed state. We show that these two ESC types differ in their regulation of genome organization due to their differential dependency on TIP5, a component of the chromatin remodeling complex NoRC. We show that TIP5 interacts on ESC chromatin with SNF2H, DNA topoisomerase 2A (TOP2A) and cohesin. TIP5 associates with sub-domains within the active A compartment that strongly intersect through long-range contacts in ESCs. We found that only ground-state chromatin requires TIP5 to limit the invasion of active domains into repressive compartments. Depletion of TIP5 increased chromatin accessibility particularly at B compartments and decreased their repressive features. Furthermore, TIP5 acts as a barrier for the repressive H3K27me3 spreading, a process that also requires TOP2A activity. Finally, ground-state ESCs require TIP5 for growth, differentiation capacity, and correct expression of developmental genes. Our results revealed the propensity of open and active chromatin domains to invade repressive domains, an action counteracted by chromatin remodeling and the relief of chromatin torsional stress. This effort in controlling open/active chromatin domains is required to establish active and repressed genome partitioning and preserves cell function and identity.

molecular biology↗

bioRxiv2018

Hematopoietic Stem And Progenitor Cells Use Podosomes To Transcellularly Home To The Bone Marrow.

Bone marrow (BM) endothelium plays an important role in homing of hematopoietic stem and progenitor cells (HSPCs) upon transplantation, but surprisingly little is known on how endothelial cells regulate local permeability and HSPC transmigration. We show that temporal loss of VE-cadherin function promotes vascular permeability in BM, even upon low dose irradiation and strongly enhanced homing of transplanted HSPCs to BM of irradiated mice. Intriguingly, stabilizing junctional VE-cadherin in vivo reduced BM permeability, but did not prevent HSPC migration into the BM, suggesting that HSPCs enter the bone marrow by transcellularly crossing the endothelium. Indeed, HSPCs induce podosomes to cross human BM endothelial monolayers in a transcellular manner. By contrast, HSPC rather use the paracellular route when VE-cadherin function is inhibited. Taken together, VE-cadherin is crucial for BM vascular homeostasis and HSPC homing, and may therefore serve as a potential therapeutic target to improve HSPC homing strategies.

cell biology↗