Mutations in NIPBL are the major cause of Cornelia de Lange Syndrome (CdLS). NIPBL is the cohesin-loading factor and has recently been associated with the BET (bromodomains and extra-terminal (ET) domain) proteins BRD2 and BRD4. Related to this, a CdLS-like phenotype has been described associated to BRD4 mutations. Here, we show direct interaction of NIPBL with different BET members in yeast, and selective interaction with BRD4 in cells, being the ET domain involved in the interaction. To understand the relationship between NIPBL and BET proteins, we have performed RNA-Seq expression analysis following depletion of the different proteins. Results indicate that genes regulated by NIPBL largely overlap with those regulated by BRD4 but not with those regulated by BRD2. ChIP-Seq analysis indicates preferential NIPBL occupancy at promoters, and knockdown experiments show mutual stabilization of NIPBL and BRD4 on co-regulated promoters. Moreover, human fibroblasts from CdLS probands with mutations in NIPBL show reduced BRD4 at co-occupied promoters. Functional analysis in vivo, using mutants of Drosophila melanogaster , confirmed the genetic interaction between Nipped-B and fs(1)h , the orthologs of human NIPBL and BRD4 , respectively. Thus, we provide evidence for NIPBL and BRD4 cooperation in transcriptional regulation, which should contribute to explain the recently observed CdLS-like phenotype associated with BRD4 mutations.

In recent years, many genes have been associated with chromatinopathies classified as “Cornelia de Lange Syndrome‐like.” It is known that the phenotype of these patients becomes less recognizable, overlapping to features characteristic of other syndromes caused by genetic variants affecting different regulators of chromatin structure and function. Therefore, Cornelia de Lange syndrome diagnosis might be arduous due to the seldom discordance between unexpected molecular diagnosis and clinical evaluation. Here, we review the molecular features of Cornelia de Lange syndrome, supporting the hypothesis that “CdLS‐like syndromes” are part of a larger “rare disease family” sharing multiple clinical features and common disrupted molecular pathways.

Cornelia de Lange Syndrome (CdLS) is a choesinopathy: a severe genetic disorder caused by mutations in the cohesin complex genes. The phenotype is characterized by typical facial dysmorphism, growth impairment and multiorgan abnormalities including brain alterations. Wnt pathway is known to play a fundamental role in central nervous system development and it has been shown that Wnt pathway is disrupted in CdLS animal models and patients cells. In this review we investigate the possible link between Wnt pathway disruption and brain abnormalities in Cornelia de Lange Syndrome as such molecular impairment could lead to an abnormal embryonic development resulting in brain abnormalities (i.e. microcephaly, cerebellar hypoplasia, abnormal cortical development) in patients with Cornelia de Lange Syndrome.

Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin. Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.

KMT2A (Lysine methyltransferase 2A) is a member of the epigenetic machinery, encoding a lysine methyltransferase responsible for the transcriptional activation through lysine 4 of histone 3 (H3K4) methylation. KMT2A has a crucial role in gene expression, thus it is associated to pathological conditions when found mutated. KMT2A germinal mutations are associated to Wiedemann–Steiner syndrome and also in patients with initial clinical diagnosis of several other chromatinopathies (i.e., Coffin–Siris syndromes, Kabuki syndrome, Cornelia De Lange syndrome, Rubinstein–Taybi syndrome), sharing an overlapping phenotype. On the other hand, KMT2A somatic mutations have been reported in several tumors, mainly blood malignancies. Due to its evolutionary conservation, the role of KMT2A in embryonic development, hematopoiesis and neurodevelopment has been explored in different animal models, and in recent decades, epigenetic treatments for disorders linked to KMT2A dysfunction have been extensively investigated. To note, pharmaceutical compounds acting on tumors characterized by KMT2A mutations have been formulated, and even nutritional interventions for chromatinopathies have become the object of study due to the role of microbiota in epigenetic regulation.

Cornelia de Lange Syndrome (CdLS), which is reported to affect about 1 in 10,000 to 30,000 newborns, is a multisystem organ developmental disorder with relatively mild to severe effects. Among others, intellectual disability represents an important feature of this condition.Cornelia de Lange syndrome can result from mutations in at least five genes: NIPBL (nipped-B-like protein), SMC1A (structural maintenance of chromosomes 1A), SMC3 (structural maintenance of chromosomes 3), RAD21 (RAD21 Cohesin Complex Component), and HDAC8 (Histone deacetylase 8). It is believed that mutations in these genes cause CdLS by impairing the function of the cohesin complex (to which all the aforementioned genes contribute to the structure or function), disrupting gene regulation during critical stages of early development.Since intellectual disorder might result from alterations in neural development, in this work, we studied the role of Hdac8 gene in mouse neural stem cells and in vertebrate (D.rerio) brain development by knock-down and chemical inhibition experiments. An underlying features of Hdac8 deficiency is an increased cell death in the developing neural tissues, either in mouse NSCs and in zebrafish embryos.

The short-chain fatty acid butyrate, produced by the gut microbiota, acts as a potent histone deacetylase (HDAC) inhibitor. We assessed possible ameliorative effects of butyrate, relative to other HDAC inhibitors, in in vitro and in vivo models of Rubinstein–Taybi syndrome (RSTS), a severe neurodevelopmental disorder caused by variants in the genes encoding the histone acetyltransferases CBP and p300. In RSTS cell lines, butyrate led to the patient-specific rescue of acetylation defects at subtoxic concentrations. Remarkably, we observed that the commensal gut microbiota composition in a cohort of RSTS patients is significantly depleted in butyrate-producing bacteria compared to healthy siblings. We demonstrate that the effects of butyrate and the differences in microbiota composition are conserved in a Drosophila melanogaster mutant for CBP, enabling future dissection of the gut–host interactions in an in vivo RSTS model. This study sheds light on microbiota composition in a chromatinopathy, paving the way for novel therapeutic interventions.

Chromatinopathies are defined as genetic disorders caused by mutations in genes coding for protein involved in the chromatin state balance. So far 82 human conditions have been described belonging to this group of congenital disorders, sharing some molecular features and clinical signs. For almost all of these conditions, no specific treatment is available. For better understanding the molecular cascade caused by chromatin imbalance and for envisaging possible therapeutic strategies it is fundamental to combine clinical and basic research studies. To this end, animal modelling systems represent an invaluable tool to study chromatinopathies. In this review, we focused on available data in the literature of animal models mimicking the human genetic conditions. Importantly, affected organs and abnormalities are shared in the different animal models and most of these abnormalities are reported as clinical manifestation, underlying the parallelism between clinics and translational research.