Physical activity practiced at a young age is associated with a less severe subsequent clinical presentation in facioscapulohumeral muscular dystrophy.

Background: In facioscapulohumeral muscular dystrophy (FSHD), it is not known whether physical activity (PA) practiced at young age is associated with the clinical presentation of disease. To assess this issue, we performed a retrospective cohort study concerning the previous practice of sports and, among them, those with medium-high cardiovascular commitment in clinically categorized carriers of a D4Z4 reduced allele (DRA).

Methods: People aged between 18 and 60 were recruited as being DRA carriers.

The FSHD jigsaw: are we placing the tiles in the right position?

Purpose Of Review: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies, involving over 870,000 people worldwide and over 20 FSHD national registries. Our purpose was to summarize the main objectives of the scientific community on this topic and the moving trajectories of research from the past to the present.

Recent Findings: To date, research is mainly oriented toward deciphering the molecular and pathogenetic basis of the disease by investigating DUX4-mediated muscle alterations.

De novo variants and recombination at 4q35: Hints for preimplantation genetic testing in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the deletion of an integral number of 3.3 kb units of the polymorphic D4Z4 repeat array at 4q35. The prenatal identification of this defect can be carried out on chorionic villi or amniocytes, whereas preimplantation genetic testing for monogenic disorders (PGT-M) requires molecular markers linked to the D4Z4 allele of reduced size.

Counseling and prenatal diagnosis in facioscapulohumeral muscular dystrophy: A retrospective study on a 13-year multidisciplinary approach.

Background And Aims: This is the first national population-based report about prenatal diagnosis for families with a history of facioscapulohumeral muscular dystrophy (FSHD), a complex hereditary disease. The incomplete disease penetrance and the phenotypic heterogeneity observed in carriers of D4Z4 alleles of reduced size, the FSHD molecular hallmark, make the estimate of genetic risk problematic.

Methods: We considered all requests of preconception counseling and prenatal diagnosis received between January 2008 and December 2020 by the genetic counseling service associated with the Italian National Registry for FSHD (INRF).

The Italian National Registry for FSHD: an enhanced data integration and an analytics framework towards Smart Health Care and Precision Medicine for a rare disease.

Background: The Italian Clinical network for FSHD (ICNF) has established the Italian National Registry for FSHD (INRF), collecting data from patients affected by Facioscapulohumeral dystrophy (FSHD) and their relatives. The INRF has gathered data from molecular analysis, clinical evaluation, anamnestic information, and family history from more than 3500 participants.

Methods: A data management framework, called Mediator Environment for Multiple Information Sources (MOMIS) FSHD Web Platform, has been developed to provide charts, maps and search tools customized for specific needs.

Interpretation of the Epigenetic Signature of Facioscapulohumeral Muscular Dystrophy in Light of Genotype-Phenotype Studies.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by incomplete penetrance and intra-familial clinical variability. The disease has been associated with the genetic and epigenetic features of the D4Z4 repetitive elements at 4q35. Recently, D4Z4 hypomethylation has been proposed as a reliable marker in the FSHD diagnosis.

Does DNA Methylation Matter in FSHD?

Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable marker in the FSHD diagnostic procedure. We considered the assessment of D4Z4 DNA methylation status conducted on distinct cohorts using different methodologies.

An autoregulatory loop controls the expression of the transcription factor NF-Y.

The heterotrimeric NF-Y complex is a pioneer factor that binds to CCAAT-genes and regulates their transcription. NF-Y cooperates with multiple transcription factors and co-regulators in order to positively or negatively influence gene transcription. The recruitment of NF-Y to CCAAT box is significantly enriched in cancer-associated gene promoters loci and positively correlates with malignancy.

The miR-196b miRNA inhibits the GATA6 intestinal transcription factor and is upregulated in colon cancer patients.

Objective: To explore the possible misexpression of the microRNA miR-196b in colorectal cancer (CRC) and its role in controlling the expression of GATA6, a putative target gene crucial to intestinal cell homeostasis and tumorigenesis.

Design: The expression of miR-196b was analysed by qRT-PCR in surgical resection samples from a cohort of sporadic colon cancer patients. Manipulations of miR-196b expression were performed to demonstrate its inhibition of GATA6 protein levels.

NUP98 fusion oncoproteins interact with the APC/C(Cdc20) as a pseudosubstrate and prevent mitotic checkpoint complex binding.

NUP98 is a recurrent partner gene in translocations causing acute myeloid leukemias and myelodisplastic syndrome. The expression of NUP98 fusion oncoproteins has been shown to induce mitotic spindle defects and chromosome missegregation, which correlate with the capability of NUP98 fusions to cause mitotic checkpoint attenuation. We show that NUP98 oncoproteins physically interact with the APC/C(Cdc20) in the absence of the NUP98 partner protein RAE1, and prevent the binding of the mitotic checkpoint complex to the APC/C(Cdc20).

MicroRNA-196b is transcribed from an autonomous promoter and is directly regulated by Cdx2 and by posterior Hox proteins during embryogenesis.

The miR-196 miRNA gene family located within the Hox gene clusters has been shown to function during embryogenesis and to be aberrantly expressed in various malignancies, including leukaemia, melanoma, and colorectal cancer. Despite its involvement in numerous biological processes, the control of miR-196 expression is still poorly defined. We identified the miR-196b promoter and found that the mature miR-196b originates from a large, non-coding primary transcript, which starts within an autonomous TATA box promoter and is not in physical continuity with either the Hoxa10 or Hoxa9 main primary transcripts.

MafB is a downstream target of the IL-10/STAT3 signaling pathway, involved in the regulation of macrophage de-activation.

In spite of the numerous reports implicating MafB transcription factor in the molecular control of monocyte-macrophage differentiation, the precise genetic program underlying this activity has been, to date, poorly understood. To clarify this issue, we planned a number of experiments that were mainly conducted on human primary macrophages. In this regard, a preliminary gene function study, based on MafB inactivation and over-expression, indicated MMP9 and IL-7R genes as possible targets of the investigated transcription factor.

NUP98 fusion oncoproteins promote aneuploidy by attenuating the mitotic spindle checkpoint.

NUP98 is a recurrent fusion partner in chromosome translocations that cause acute myelogenous leukemia. NUP98, a nucleoporin, and its interaction partner Rae1, have been implicated in the control of chromosome segregation, but their mechanistic contributions to tumorigenesis have been unclear. Here, we show that expression of NUP98 fusion oncoproteins causes mitotic spindle defects and chromosome missegregation, correlating with the capability of NUP98 fusions to cause premature securin degradation and slippage from an unsatisfied spindle assembly checkpoint (SAC).

The Orosomucoid 1 protein is involved in the vitamin D - mediated macrophage de-activation process.

Orosomucoid 1 (ORM1), also named Alpha 1 acid glycoprotein A (AGP-A), is an abundant plasma protein characterized by anti-inflammatory and immune-modulating properties. The present study was designed to identify a possible correlation between ORM1 and Vitamin D3 (1,25(OH)2D3), a hormone exerting a widespread effect on cell proliferation, differentiation and regulation of the immune system. In particular, the data described here indicated that ORM1 is a 1,25(OH)2D3 primary response gene, characterized by the presence of a VDRE element inside the 1kb sequence of its proximal promoter region.

HOXD13 binds DNA replication origins to promote origin licensing and is inhibited by geminin.

HOX DNA-binding proteins control patterning during development by regulating processes such as cell aggregation and proliferation. Recently, a possible involvement of HOX proteins in replication origin activity was suggested by results showing that a number of HOX proteins interact with the DNA replication licensing regulator geminin and bind a characterized human origin of replication. The functional significance of these observations, however, remained unclear.

Hoxd13 binds in vivo and regulates the expression of genes acting in key pathways for early limb and skeletal patterning.

5' HoxD genes are required for the correct formation of limb skeletal elements. Hoxd13, the most 5'-located HoxD gene, is important for patterning the most distal limb region, and its mutation causes human limb malformation syndromes. The mechanisms underlying the control of developmental processes by Hoxd13, and by Hox genes in general, are still elusive, due to the limited knowledge on their direct downstream target genes.

Pbx1/Pbx2 requirement for distal limb patterning is mediated by the hierarchical control of Hox gene spatial distribution and Shh expression.

Vertebrate limb development occurs along three cardinal axes-proximodistal, anteroposterior and dorsoventral-that are established via the organization of signaling centers, such as the zone of polarizing activity (ZPA). Distal limb development, in turn, requires a molecular feedback loop between the ZPA expression of sonic hedgehog (Shh) and the apical ectodermal ridge. The TALE homeoprotein Pbx1 has been shown to be essential for proximal limb development.

Hoxd13 and Hoxa13 directly control the expression of the EphA7 Ephrin tyrosine kinase receptor in developing limbs.

Hoxa and Hoxd genes, related to the Drosophila Abd-B gene, display regionally restricted expression patterns and are necessary for the formation of the limb skeletal elements. Hox genes encode transcription factors, which are supposed to control the expression of a series of downstream target genes, whose nature has remained largely elusive. Several genes were identified that are differentially expressed in relation to Hox gene activity; few studies, however, explored their direct regulation by Hox proteins.

A Pbx1-dependent genetic and transcriptional network regulates spleen ontogeny.

The genetic control of cell fate specification, morphogenesis and expansion of the spleen, a crucial lymphoid organ, is poorly understood. Recent studies of mutant mice implicate various transcription factors in spleen development, but the hierarchical relationships between these factors have not been explored. In this report, we establish a genetic network that regulates spleen ontogeny, by analyzing asplenic mice mutant for the transcription factors Pbx1, Hox11 (Tlx1), Nkx3.

Dynamic recruitment of NF-Y and histone acetyltransferases on cell-cycle promoters.

Regulation of transcription during the cell-cycle is under the control of E2 factors (E2Fs), often in cooperation with nuclear factor Y (NF-Y), a histone-like CCAAT-binding trimer. NF-Y is paradigmatic of a constitutive, ubiquitous factor that pre-sets the promoter architecture for other regulatory proteins to access it. We analyzed the recruitment of NF-Y, E2F1/4/6, histone acetyltransferases, and histone deacetylase (HDAC) 1/3/4 to several cell-cycle promoters by chromatin immunoprecipitation assays in serum-starved and restimulated NIH3T3 cells.

Interactions between p300 and multiple NF-Y trimers govern cyclin B2 promoter function.

The CCAAT box is one of the most common elements in eukaryotic promoters and is activated by NF-Y, a conserved trimeric transcription factor with histone-like subunits. Usually one CCAAT element is present in promoters at positions between -60 and -100, but an emerging class of promoters harbor multiple NF-Y sites. In the triple CCAAT-containing cyclin B2 cell-cycle promoter, all CCAAT boxes, independently from their NF-Y affinities, are important for function.