Biology subjects

Colasante, G.

Publications and source records attributed to Colasante, G..

4 recordsLinked to original sources

bioRxiv2026

Suppression of YAP/TAZ molecular targets by epigenetic editing interferes with GBM growth and invasiveness

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by extensive heterogeneity, diffuse invasion, and recurrence despite multimodal therapy. Aberrant transcriptional programs driven by oncogenic signaling pathways sustain GBM growth, stemness, and therapy resistance, yet targeting individual molecular nodes has yielded limited clinical benefit. Here, we introduce a transcriptional rewiring strategy based on an engineered epigenetic silencer factor (ESF) targeting the YAP/TAZ-TEAD axis. We developed a TEAD1 Epigenetic Silencer (TES) by fusing the DNA-binding domain of TEAD1 to repressive epigenetic modules. TES selectively binds TEAD genomic targets and imposes stable transcriptional repression of YAP/TAZ-dependent gene programs through chromatin remodeling and DNA methylation. Genome-wide analyses revealed that TES preserves TEAD1 DNA-binding specificity while converting an oncogenic transcriptional platform into a repressive state. Functionally, TES impaired proliferation, induced cell death, and reduced migratory and invasive properties in glioma cell lines and patient-derived cancer stem-like cells. In vivo, TES significantly reduced tumor growth in orthotopic GBM xenograft models and enhanced the therapeutic efficacy of temozolomide. Importantly, TES was well tolerated by normal neural cells in vitro and in the adult mouse brain in vivo. These findings establish TES as a proof-of-concept epigenetic therapy to durably suppress oncogenic transcriptional networks in GBM.

cancer biology↗

bioRxiv2022

Developmental instability of CA1 pyramidal cells in Dravet Syndrome

Dravet Syndrome (DS) is mostly caused by heterozygous loss-of-function mutations in the voltage-gated sodium channel SCN1A (Nav1.1), thought to result in severe epilepsy and neurodevelopmental impairment due to reduced interneuron excitability. Recent studies in mouse models suggest that an "interneuronopathy" alone does not completely explain all the cellular and network impairments seen in DS. Here, we investigated the development of the intrinsic, synaptic, and network properties of CA1 pyramidal cells in a DS model prior to the appearance of overt seizures. We report that CA1 pyramidal cell development is disrupted by loss of Scn1a, and propose that this is explained by a period of reduced intrinsic excitability in early postnatal life, during which Scn1a is normally expressed in hippocampal pyramidal cells. We also use a novel ex vivo model of homeostatic plasticity to show an instability in homeostatic response during DS epileptogenesis. This study provides evidence for an important role of Scn1a haploinsufficiency in pyramidal cells in the pathophysiology of DS.

neuroscience↗

bioRxiv2022

Balanced SET levels favor the correct enhancer repertoire during cell fate acquisition

Within the chromatin, distal elements interact with promoters to regulate specific transcriptional programs. Histone acetylation, interfering with the net charges of the nucleosomes, is a key player in this regulation. Here, we report that the onco-protein SET is a critical determinant for the levels of histone acetylation within enhancers. We disclose that conditions in which SET is accumulated, including the severe Schinzel-Giedion Syndrome (SGS), are characterized by a failure in the usage of the distal regulatory regions typically employed during fate commitment. This is accompanied by the usage of alternative enhancers leading to a massive rewiring of the distal control of the gene transcription. This represents a (mal)adaptive mechanism that, on one side, allows to achieve a certain degree of differentiation, while on the other affects the fine and corrected maturation of the cells. Thus, we propose the differential in cis-regulation as a contributing factor to the pathological basis of the SET-related disorders in humans, including SGS, neurodevelopmental disorders, myeloproliferative diseases, and cancer.

developmental biology↗

bioRxiv2018

CRISPRa-mediated Kcna1 upregulation decreases neuronal excitability and suppresses seizures in a rodent model of temporal lobe epilepsy

Epilepsy is a major health burden, calling for new mechanistic and therapeutic insights. CRISPR-mediated gene editing shows promise to cure genetic pathologies, although hitherto it has mostly been applied ex-vivo. Its translational potential for treating non-genetic pathologies is still unexplored. Furthermore, neurological diseases represent an important challenge for the application of CRISPR, because of the need in many cases to manipulate gene function of neurons in situ. A variant of CRISPR, CRISPRa, offers the possibility to modulate the expression of endogenous genes by directly targeting their promoters. We asked if this strategy can effectively treat acquired focal epilepsy, focusing on ion channels because their manipulation is known be effective in changing network hyperactivity and hypersynchronisation. We applied a doxycycline-inducible CRISPRa technology to increase the expression of the potassium channel gene Kcna1 (encoding Kv1.1) in mouse hippocampal excitatory neurons. CRISPRa-mediated Kv1.1 upregulation led to a substantial decrease in neuronal excitability. Continuous video-EEG telemetry showed that AAV9-mediated delivery of CRISPRa, upon doxycycline administration, decreased spontaneous generalized tonic-clonic seizures in a model of temporal lobe epilepsy, and rescued cognitive impairment and transcriptomic alterations associated with chronic epilepsy. The focal treatment minimizes concerns about off-target effects in other organs and brain areas. This study provides the proof of principle for a translational CRISPR-based approach to treat neurological diseases characterized by abnormal circuit excitability.

neuroscience↗