Biology subjects

Schreiter, F.

Publications and source records attributed to Schreiter, F..

4 recordsLinked to original sources

bioRxiv2026

Selective class IIa HDAC inhibition reverses diastolic dysfunction in cardiometabolic HFpEF

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent cardiometabolic syndrome with yet no effective therapies. Here, we report that selectively class IIa histone deacetylases (HDACs) but no other classes of HDACs are enzymatically activated in hearts from HFpEF patients and cardiometabolic HFpEF animal models. Cell type-specific and enzymatic activity-specific genetic loss-of-function models of the cardiomyocyte-enriched class IIa HDAC family member HDAC4 and the pharmacological class IIa HDAC-selective inhibitor TMP195 prevent and reverse diastolic dysfunction and exercise intolerance in cardiometabolic HFpEF in vivo. In contrast to pan-HDAC inhibition no adverse effects are observed. Despite its well-known non-enzymatic role as transcriptional repressor, we found that specifically enzymatic activation of HDAC4 has little direct effects on cardiomyocyte-intrinsic gene expression. Instead, non-epigenetic actions lead to endothelial activation via altered cardiocrine signaling. We discovered that selective enzymatic class IIa HDAC inhibition is a new therapeutic concept to combat cardiac HFpEF.

molecular biology↗

bioRxiv2025

Genomic G quadruplexes regulate mRNA splicing

Genomic G quadruplexes (G4) are non-canonical DNA structures that regulate gene expression primarily through transcriptional control. Here, we uncover that DNA G quadruplexes are critical determinants of pre-mRNA splicing. G4s on the DNA template strand serve as recruiting elements for the RNA-binding proteins SRSF9 and WBP11 in order to facilitate productive splicing of adjacent pre-mRNAs. This process is controlled by protein arginine methyltransferase 5 (PRMT5) that releases SRSF9 and WBP11 from G4s through arginine methylation. Acyl-CoA dehydrogenase very long-chain specific (ACADVL) is a gene highly regulated by this mechanism since targeting G4 stability prevents mis-splicing and restores ACADVL protein levels. In the heart, deletion of Prmt5 recapitulates defective splicing and results in progressive cardiac failure along with loss of ACADVL in mice. Importantly, we find that Acadvl regulation plays a critical role for cardiomyopathy as restoring Acadvl expression in Prmt5 knockout mice prevents cardiac dysfunction. This study establishes an unanticipated fundamental principle by which genomic G quadruplexes act as splicing enhancers of associated pre-mRNAs, and reveals an essential role in cardiac homeostasis.

cell biology↗

bioRxiv2025

Somatic Hdac4-902fs mutations lead to loss of HDAC4 function through nonsense-mediated mRNA degradation

Histone deacetylases (HDACs) are essential chromatin regulators and are involved in the regulation of gene expression by removing acetyl groups from histone and non-histone proteins. Histone deacetylase 4 (HDAC4) is known to regulate the process of endochondral ossification in mice by non-enzymatic repression of the activity of the RUNX2 transcription factor (TF) and to control cardiac metabolism in physiological stress situations. In this study, we examined the function of somatic HDAC4-902 frameshift (fs) mutations that are frequently observed in gastric and colon adenocarcinoma patients. Whether these mutations lead to a gain- or a loss-of-function is currently unknown. Here we generated a murine model bearing a germline HDAC4-methionine (M) amino acid (AA) 902-to-histidine (H) frameshift (M902Hfs) mutation. HDAC4-M902Hfs mice phenocopied HDAC4 null mice and present with premature ossification and early postnatal death. Mechanistically, we found that the HDAC4-M902Hfs mutation induced nonsense-mediated mRNA decay, resulting in loss of HDAC4 protein. This loss-of-function (LOF) effect was further supported by increased mRNA and protein expression of runt-related transcription factor-2 (RUNX2) and reduced class IIa HDAC enzymatic activity, indicating that HDAC4 contributes significantly to endogenous class IIa HDAC activity. Patient-derived data suggest that the HDAC4-902fs mutation is associated with reduced mRNA expression of HDAC4. In conclusion, our study identify that HDAC4-902fs mutation is a loss-of-function mutation, but raises the new question whether the loss of non-enzymatic mechanisms or the reduction in class IIa HDAC activity contributes to tumor progression.

cancer biology↗

bioRxiv2023

Genetic Loss of Nicotinamide Nucleotide Transhydrogenase Prevents from Cardiometabolic Heart Failure with Preserved Ejection Fraction

RationaleHeart failure with preserved ejection fraction (HFpEF) represents a common clinical endpoint of cardiometabolic diseases which impair myocardial diastolic relaxation. Although myocardial redox perturbations are known to accompany HFpEF, the specific role of mitochondrial oxidative stress has not been demonstrated yet. ObjectiveBased on an observation that C57BL6/N - but not C57BL6/J - mice develop diastolic dysfunction when provided an ad libitum high-fat and 0.5% N({omega})-nitro-L-arginine methyl ester (HFD+L-NAME) diet, we conducted a multi-cohort murine study to determine whether the loss of Nicotinamide Nucleotide Transhydrogenase (NNT), a mitochondrial transhydrogenase that couples NADPH:NADP+ to NADH:NAD+ homeostasis, protects mice from developing cardiometabolic alterations. Methods and ResultsTwo cohorts of 12-week-old male and female mice possessing wild-type (Nnt+/+) or deleted (Nnt-/-) NNT were challenged by HFD+L-NAME for 9 weeks (n = 6-10). Male Nnt+/+ mice developed obesity (23.2% {Delta}, P = 0.003), arterial hypertension (24 {+/-} 5 {Delta} mmHg, P = 0.023), impaired glucose tolerance (P = 0.006), and reduced maximal treadmill running distance (-172 {+/-} 73.1 {Delta} m, P = 0.006) following 9 weeks HFD+L-NAME, whereas male Nnt-/- mice did not. Female mice were protected from cardiometabolic dysfunction regardless of Nnt genotype. Cardiac functional and morphologic characterization revealed similar NNT-dependent and sex-specific increases in E/e (42.8 vs. 21.5, P < 0.001) and E/A (2.3 vs 1.4, P = 0.007) ratios, diastolic stiffness (0.09 vs 0.04 mmHg/L, P = 0.02), and myocardial fibrosis (P = 0.02). Unsupervised transcriptomic analysis identified distinct genetic and dietary signatures, wherein Nnt+/+ exhibited disproportionate perturbations in various mitochondrial oxidative pathways following HFD+L-NAME. Our search for putative transcriptional regulators identified NNT-dependent suppression of NAD+ dependent deacetylase Sirt3. ConclusionsTaken together, these observations support that the genetic disruption of Nnt protects against both cardiac and metabolic consequences of HFD+L-NAME, thus highlighting a novel etiology-specific avenue for HFpEF therapeutics.

physiology↗