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Hypoparathyroidism in pediatric patients
Published in Pallavi Iyer, Herbert Chen, Thyroid and Parathyroid Disorders in Children, 2020
Andrew C. Calabria, Michael A. Levine
Hypoparathyroidism can be a component of the Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies/deafness (CHARGE) syndrome. More than 75% of cases are due to heterozygous loss-of-function mutations in the coding region of the CHD7 gene at chromosome 8q12.2. CHD7 is a chromodomain helicase DNA binding protein and is active in chromatin remodeling. Mutations are usually de novo but rarely are inherited in an autosomal dominant manner. Less commonly, CHARGE syndrome can be due to abnormalities in semaphoring 3E (Semaphorin 3E), which controls cell positioning during embryonic development on chromosome 7q21.11. There is significant clinical overlap with DGS, as both conditions display hypoparathyroidism, cardiac anomalies, cleft palate, renal anomalies, ear abnormalities/deafness, and developmental delay. In fact, hypoparathyroidism may be more common in newborns with CHARGE syndrome compared to newborns with DGS (3).
DNA Methylation and Epigenetics: New Developments in Biology and Treatment
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Jesus Duque, Michael Lübbert, Mark Kirschbaum
H3K9 methylation, particularly trimethylation, is believed to be crucial to formation of heterochromatin (80), particularly as this methylation creates a binding site for the chromodomain (chromatin organization modifier) of the repression related protein HP1. Trimethylation at H3K9 is achieved by Suv39h1/Suv39h2 (94) which was the first HMT identified. This process is involved in several tumor-related signaling pathways, such as suppression achieved by Smads after TGF-b signaling (95), or suppression of cyclin E and E2F by Rb protein, the latter losing this suppressive ability when mutated (96,97). Relevant to our argument is that this repression requires the recruitment of HDACs (98). Furthermore, it appears that this Suv39h-HP1-mediated mechanism is intimately involved with DNMT3A and DNMT3B DNA methylating activity (99). It is worth noting that mice with decreased levels of Suv39h1 showed a high incidence of B-cell lymphomas (94). Of particular interest with regard to leukemia, it has been shown that residues 380–432 and 351–381 in the RUNX1 transcription factor, bind Suv39h1 as well as HDAC1 and 3 (100). RUNX1 is a component of fusion proteins found frequently in AML, such as t(8;21), t(12;21), and related to the activity inv(16); this relationship to H3K9 methylation may explain the release of lysosomal repression in cells with these mutations upon treatment with HDACi and hypomethylating agents (101). SETDB1, another enzyme which di- and trimethylates histones at H3K9, also interacts directly with DNMT3A and DNMT3B (102).
Immunology (primary Immunodeficiency Syndromes
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephan Strobel, Alison M. Jones
DiGeorge syndrome refers to the complex of hypoparathyroidism, congenital heart disease, cleft lip/palate and absent thymus, and represents the severe end of the spectrum of disorders caused by chromosome 22q11 microdeletion syndrome. The ‘complete’ form with absent T-cells is very rare, while there is a wide spectrum of less severe immunodeficiencies in other affected children. It is caused by a hemizygous microdeletion of chromosome 22q11, inherited as an autosomal dominant trait, but many cases arise as new mutations. A similar thymic defect is associated with various other complex syndromes, the most common being CHARGE syndrome, caused by mutations in CHD7 (chromodomain helicase DNA binding protein 7).
Novel chromobox 2 inhibitory peptide decreases tumor progression
Published in Expert Opinion on Therapeutic Targets, 2023
Lindsay W. Brubaker, Donald S. Backos, Vu T. Nguyen, Philip Reigan, Tomomi M Yamamoto, Elizabeth R. Woodruff, Ritsuko Iwanaga, Michael F. Wempe, Vijay Kumar, Christianne Persenaire, Zachary L. Watson, Benjamin G. Bitler
With the success of prior PRC1 inhibitors and the impact of CBX2 modulation in HGSOC, we developed CBX2 inhibitory peptides. While there is literature describing a ligand targeting the chromodomain of CBX2, which demonstrated efficacy in blocking neuroendocrine differentiation in prostate cancer cell lines [21] and decreased cell proliferation in vitro in triple negative breast cancer [22], given the unique chromodomain and A/T hook region, of CBX2, we felt there was room for improved selectivity. In this report, we detail the construction of a homology model of the CBX2 structure, that allowed us to target these unique regions of the protein with high predicted specificity compared to other CBX proteins. Multiple peptides were generated and evaluated for CBX2 binding and anti-proliferative efficacy in a panel of HGSOC cell models and our most promising peptide significantly inhibited xenograft tumor growth.
Hypoplastic left heart syndrome (HLHS): molecular pathogenesis and emerging drug targets for cardiac repair and regeneration
Published in Expert Opinion on Therapeutic Targets, 2021
Anthony T Bejjani, Neil Wary, Mingxia Gu
Other cardiac cell types besides cardiomyocytes are also instrumental for proper cardiogenesis, including endocardial cells, fibroblasts, and epicardial cells. These cells provide necessary signals that direct different aspects of the heart development and cardiomyocyte maturation. Endocardial cells are a source of mesenchymal cells that contribute to parts of the valves and septa of the heart [55]. Moreover, they produce signals that mediate the trabeculation of the chambers during development [21,56]. This cell population was shown to be reduced in patients with HLHS [57]. Recently, Miao et al. characterized an impaired endocardial cell population in HLHS patients using single-cell RNA sequencing and showed that several transcription factors were downregulated in patient iPSC derived endocardial cells compared to controls such as ETS proto-oncogene 1 (ETS1), which is known to be associated with HLHS [30]. Additionally, chromatin remodelers such as Chromodomain-helicase-DNA-binding including protein (CHD7) were also downregulated [58]. Fibronectin 1 (FN1) was downstream of the ETS1 in the endocardium, which decreased cardiomyocyte proliferation and possibly contributed to the ventricular hypoplasia [58,59]. More studies are needed to assess the roles of non-cardiomyocyte cell populations in CHDs.
Beyond EZH2: is the polycomb protein CBX2 an emerging target for anti-cancer therapy?
Published in Expert Opinion on Therapeutic Targets, 2019
Maïka Jangal, Benjamin Lebeau, Michael Witcher
The chromodomain of CBX paralogues carries an H3K27me3 recognition module dependent on a hydrophobic, aromatic cage that coordinates interaction with the epigenetic modification [36]. The structure of the rigid aromatic cage is conserved between the CBX family members, but variability exists among the hydrophobic amino acids that interact with H3K27me3 [102]. For example, across the CBX family, Phe11, Trp32 and Trp35 play a critical role in coordinating their capacity to act as readers of methylation and are thus highly conserved. Within CBX4 and CBX7, the hydrophobic residues Val10, Leu49 and Val13, also enhance the recognition of lysine methylation whereas in CBX2, CBX6 and CBX8 Val13 is replaced by Ala13 [102]. The CBX pocket module is variable, whether free or bound, indicating a dynamic structure that may complicate the discovery of small molecule inhibitors.