Biology subjects

Cecere, F.

Publications and source records attributed to Cecere, F..

3 recordsLinked to original sources

bioRxiv2025

Identification of genetic and non-genetic modifiers of genomic imprinting through whole genome screening in humans

Genomic imprinting is required for normal development, and abnormal methylation of differentially methylated regions (iDMRs) controlling the parent of origin-dependent expression of the imprinted genes has been found in constitutional disorders affecting growth, metabolism, neurobehavior, and in cancer. In most of these cases the cause of the imprinting abnormalities is unknown. Also, these studies have generally been performed on a limited number of CpGs, and a systematic investigation of iDMR methylation in the general population is lacking. By analysing the iDMRs in a large number of peripheral blood DNA methylation array datasets of unaffected individuals and patients with rare disorders, we determined the most common iDMR methylation profiles and identified many genetic and non-genetic factors contributing to their variability. We found that methylation variability is not homogeneous within the iDMRs and that the CpGs closer to the ZFP57 binding sites are less susceptible to methylation changes. We demonstrated the methylation polymorphism of three iDMRs and the atypical behaviour of several others, and reported the association of 25 disease- and 47 non-disease-complex traits, including blood cell type composition, as well as 15 mendelian or chromosomal disorders, with iDMR methylation changes in blood DNA. These findings identify several genetic and non-genetic factors associated with genomic imprinting maintenance in humans, which may have a role in the aetiology of the diseases associated with imprinting abnormalities and have clear implications in molecular diagnostics.

genetics↗

bioRxiv2024

A novel iPSC-based model of ICF syndrome subtype 2 recapitulates the molecular phenotype of ZBTB24 deficiency

Immunodeficiency, Centromeric instability and Facial anomalies (ICF) syndrome is a rare genetic disorder characterized by variable immunodeficiency. More than half of the affected individuals show mild to severe intellectual disability at early onset. This disorder is genetically heterogeneous and ZBTB24 is the causative gene of the subtype 2, accounting for about 30% of the ICF cases. ZBTB24 is a multifaceted transcription factor belonging to the Zinc-finger and BTB domain-containing protein family, which are key regulators of developmental processes. Aberrant DNA methylation is the main molecular hallmark of ICF syndrome. The functional link between ZBTB24 deficiency and DNA methylation errors is still elusive. Here, we generated a novel ICF2 disease model by deriving induced pluripotent stem cells (iPSCs) from peripheral CD34+-blood cells of a patient homozygous for the p.Cys408Gly mutation, the most frequent missense mutation in ICF2 patients and which is associated with a broad clinical spectrum. The mutation affects a conserved cysteine of the ZBTB24 zinc-finger domain, perturbing its function as transcriptional activator. ICF2-iPSCs recapitulate the methylation defects associated with ZBTB24 deficiency, including centromeric hypomethylation. We validated that the mutated ZBTB24 protein loses its ability to directly activate expression of CDCA7 and other target genes in the patient-derived iPSCs. Upon hematopoietic differentiation, ICF2-iPSCs showed decreased vitality and a lower percentage of CD34+/CD43+/CD45+ progenitors. Overall, the ICF2-iPSC model is highly relevant to explore the role of ZBTB24 in DNA methylation homeostasis and provides a tool to investigate the early molecular events linking ZBTB24 deficiency to the ICF2 clinical phenotype.

genetics↗

bioRxiv2023

A maternal-effect Padi6 variant results in abnormal nuclear localization of DNMT1 and failure of epigenetic reprogramming and zygotic genome activation in mouse embryos

PADI6 belongs to the multi-protein sub-cortical maternal complex (SCMC) that is present specifically in mammalian oocytes and early embryos. Maternal inactivation of SCMC genes generally results in early embryo lethality. In humans, variants in a subset of SCMC genes have been found in the healthy mothers of children affected by genomic imprinting disorders and characterized by multi-locus imprinting disturbances (MLID). However, how the SCMC controls the DNA methylation required to regulate imprinting remains poorly defined. To address this issue, we generated a mouse line carrying a Padi6 missense variant that had been identified in the mother of two sisters affected by Beckwith-Wiedemann syndrome and MLID. We found that if homozygous in female mice this variant resulted in interruption of embryo development at the 2-cell stage. Single-cell DNA methylation and RNA analyses demonstrated genomic hypermethylation, down-regulation of zygotic genome activation (ZGA) genes and up-regulation of maternal decay genes in 2-cell embryos from homozygous females. In addition, immunofluorescence analysis showed abnormal localization of DNMT1 and UHRF1 in mutant oocytes and zygotes. Taken together, this study demonstrates that PADI6 controls the subcellular localization of DNMT1 that is necessary for pre-implantation epigenetic reprogramming and ZGA.

genomics↗