1. Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome
Marjolein J A Weerts, et al. Genet Med. 2021 Nov;23(11):2122-2137. doi: 10.1038/s41436-021-01246-2. Epub 2021 Aug 3.
Purpose: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.
2. SETD5-Coordinated Chromatin Reprogramming Regulates Adaptive Resistance to Targeted Pancreatic Cancer Therapy
Zhentian Wang, et al. Cancer Cell. 2020 Jun 8;37(6):834-849.e13. doi: 10.1016/j.ccell.2020.04.014. Epub 2020 May 21.
Molecular mechanisms underlying adaptive targeted therapy resistance in pancreatic ductal adenocarcinoma (PDAC) are poorly understood. Here, we identify SETD5 as a major driver of PDAC resistance to MEK1/2 inhibition (MEKi). SETD5 is induced by MEKi resistance and its deletion restores refractory PDAC vulnerability to MEKi therapy in mouse models and patient-derived xenografts. SETD5 lacks histone methyltransferase activity but scaffolds a co-repressor complex, including HDAC3 and G9a. Gene silencing by the SETD5 complex regulates known drug resistance pathways to reprogram cellular responses to MEKi. Pharmacological co-targeting of MEK1/2, HDAC3, and G9a sustains PDAC tumor growth inhibition in vivo. Our work uncovers SETD5 as a key mediator of acquired MEKi therapy resistance in PDAC and suggests a context for advancing MEKi use in the clinic.
3. Histone acetylases--versatile players
Y Nakatani Genes Cells. 2001 Feb;6(2):79-86. doi: 10.1046/j.1365-2443.2001.00411.x.
Genomic DNA in eukaryotes is tightly packed in the form of a highly ordered chromatin structure. In view of this tight packing, one of the most important questions in biology is how the transcriptional machinery regulates target genes in chromatin. Reversible modification of histones by acetylation is involved in transcriptional activation as well as repression in chromatin contexts. Recent studies with highly purified histone acetylases have provided insights into the mechanisms whereby acetylases contribute to transcriptional control. Furthermore, they suggest the possibility that histone acetylases could play roles in various forms of DNA metabolism as well as in transcription in chromatin contexts.
