Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis

Zebrafish brd2a and brd2b are paralogous members of the bromodomain-ET (BET) family of transcriptional coregulators that show structural and expression divergence

<p>Abstract</p> <p>Background</p> <p>Brd2 belongs to the bromodomain-extraterminal domain (BET) family of transcriptional co-regulators, and functions as a pivotal histone-directed recruitment scaffold in chromatin modification complexes affecting signal-dependent transcription. Brd2 facilitates expression of genes promoting proliferation and is implicated in apoptosis and in egg maturation and meiotic competence in mammals; it is also a susceptibility gene for juvenile myoclonic epilepsy (JME) in humans. The <it>brd2 </it>ortholog in <it>Drosophila </it>is a maternal effect, embryonic lethal gene that regulates several homeotic loci, including Ultrabithorax. Despite its importance, there are few systematic studies of <it>Brd2 </it>developmental expression in any organism. To help elucidate both conserved and novel gene functions, we cloned and characterized expression of <it>brd2 </it>cDNAs in zebrafish, a vertebrate system useful for genetic analysis of development and disease, and for study of the evolution of gene families and functional diversity in chordates.</p> <p>Results</p> <p>We identify cDNAs representing two paralogous <it>brd2 </it>loci in zebrafish, <it>brd2a </it>on chromosome 19 and <it>brd2b </it>on chromosome 16. By sequence similarity, syntenic and phylogenetic analyses, we present evidence for structural divergence of <it>brd2 </it>after gene duplication in fishes. <it>brd2 </it>paralogs show potential for modular domain combinations, and exhibit distinct RNA expression patterns throughout development. RNA <it>in situ </it>hybridizations in oocytes and embryos implicate <it>brd2a </it>and <it>brd2b </it>as maternal effect genes involved in egg polarity and egg to embryo transition, and as zygotic genes important for development of the vertebrate nervous system and for morphogenesis and differentiation of the digestive tract. Patterns of <it>brd2 </it>developmental expression in zebrafish are consistent with its proposed role in <it>Homeobox </it>gene regulation.</p> <p>Conclusion</p> <p>Expression profiles of zebrafish <it>brd2 </it>paralogs support a role in vertebrate developmental patterning and morphogenesis. Our study uncovers both maternal and zygotic contributions of <it>brd2</it>, the analysis of which may provide insight into the earliest events in vertebrate development, and the etiology of some forms of epilepsy, for which zebrafish is an important model. Knockdowns of <it>brd2 </it>paralogs in zebrafish may now test proposed function and interaction with homeotic loci in vertebrates, and help reveal the extent to which functional novelty or partitioning has occurred after gene duplication.</p

2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results. One possible avenue is the development of patient-derived models, e.g. by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), which can then be differentiated into any cell type for modelling. These systems contain key genetic information from the donors, and therefore have enormous potential as tools in the investigation of pathological mechanisms underlying disease phenotype, and progression, as well as in drug testing platforms. hiPSCs have been widely cultured in 2D systems, but in order to mimic human brain complexity, 3D models have been proposed as a more advanced alternative. This review will focus on the use of patient-derived hiPSCs to model AD, PD, HD and ALS. In brief, we will cover the available stem cells, types of 2D and 3D culture systems, existing models for neurodegenerative diseases, obstacles to model these diseases in vitro, and current perspectives in the field

Review of disrupted sleep patterns in Smith-Magenis syndrome and normal melatonin secretion in a patient with an atypical interstitial 17p11.2 deletion.

International audienceSmith-Magenis syndrome (SMS) is a disorder characterized by multiple congenital anomalies and behavior problems, including abnormal sleep patterns. It is most commonly due to a 3.5 Mb interstitial deletion of chromosome 17 band p11.2. Secretion of melatonin, a hormone produced by the pineal gland, is the body's signal for nighttime darkness. Published reports of 24-hr melatonin secretion patterns in two independent SMS cohorts (US and France) document an inverted endogenous melatonin pattern in virtually all cases (96%), suggesting that this finding is pathognomic for the syndrome. We report on a woman with SMS due to an atypical large proximal deletion ( approximately 6Mb; cenTNFRSFproteinB) of chromosome band (17)(p11.2p11.2) who presents with typical sleep disturbances but a normal pattern of melatonin secretion. We further describe a melatonin light suppression test in this patient. This is the second reported patient with a normal endogenous melatonin rhythm in SMS associated with an atypical large deletion. These two patients are significant because they suggest that the sleep disturbances in SMS cannot be solely attributed to the abnormal diurnal melatonin secretion versus the normal nocturnal pattern

Zebrafish and are paralogous members of the bromodomain-ET (BET) family of transcriptional coregulators that show structural and expression divergence-8

S through ovaries are shown in E-J. maternal RNAs are dispersed and abundant in stage I and II oocytes (A, E), and are sometimes found inside the germinal vesicle (gv), as in G (see small oocytes at far right). By stage III,transcripts accumulate around the outside of the germinal vesicle and rather unevenly around the periphery of the cortex just inside the vitelline envelope (C, E; G, arrowheads). RNAs then localize around the periphery of the cortex by late stage III, early stage IV (I, arrowheads). RNAs are also present in follicle cells of stage III/IV oocytes (C; G, I, arrowheads outside oocyte). Although maternal transcripts are also dispersed throughout stage I and II oocytes, and often found inside the germinal vesicle (B, F, H, J), in contrast to , they become strictly localized to the region surrounding the micropyle (D, mp; H, J, arrowheads), the future animal pole, sometime during stage III, and are not expressed in follicle cells. A,B: 40X; C-F: 80X; G-J, 100X.<p><b>Copyright information:</b></p><p>Taken from "Zebrafish and are paralogous members of the bromodomain-ET (BET) family of transcriptional coregulators that show structural and expression divergence"</p><p>http://www.biomedcentral.com/1471-213X/8/39</p><p>BMC Developmental Biology 2008;8():39-39.</p><p>Published online 10 Apr 2008</p><p>PMCID:PMC2373290.</p><p></p

Zebrafish and are paralogous members of the bromodomain-ET (BET) family of transcriptional coregulators that show structural and expression divergence-2

S (lower) added to branches. At least one duplication of the gene has occurred in teleosts. zf626/zf619 cDNAs group with in zebrafish, while zf69 cDNA groups with sequences from the paralogous locus. zf626, GenBank: ; zf619, GenBank: ; zf69, GenBank: ; , GenBank: ; , GenBank: .2; chr16.1, 16.2, 16.3, from Ensembl: ENSDARG00000046087; , GenBank: ; , GenBank: ; , GenBank: ; , GenBank: ; , GenBank: ; , GenBank: ; , GenBank: ; , Ensembl: SINFRUG00000151665; , EMBL: ; , Ensembl: SINFRUG00000141925; , Ensembl: SINFRUG00000145405; , Ensembl: SINFRUG00000148459; , Ensembl: SINFRUG00000151665; , EMBL: ; , EMBL: ; , EMBL: ; , EMBL: ; , EMBL: ; , EMBL: ; , GenBank: ; , Ensembl: ENSORLG00000016659; , Ensembl: ENSORLG00000006490; , Ensembl: ENSORLG00000010329; , Ensembl: ENSORLG00000013915; , Ensembl: ENSORLG00000012190; , Ensembl: ENSORLG00000016149; , GenBank ; , EMBL: ; , GenBank: ; , GenBank: ; , EMBL: ; , EMBL: GenBank: ; , GenBank: ; , GenBank: .1; , Ensembl: ENSGALG00000013295; , Ensembl: ENSGALG00000006031; , GenBank: ; , GenBank: ; , GenBank: ; , GenBank: ; , GenBank: ; , GenBank: ; , GenBank: ; , GenBank: ; , GenBank: ;, GenBank: ; , GenBank: ; , GenBank: ; , GenBank: ; , GenBank: .<p><b>Copyright information:</b></p><p>Taken from "Zebrafish and are paralogous members of the bromodomain-ET (BET) family of transcriptional coregulators that show structural and expression divergence"</p><p>http://www.biomedcentral.com/1471-213X/8/39</p><p>BMC Developmental Biology 2008;8():39-39.</p><p>Published online 10 Apr 2008</p><p>PMCID:PMC2373290.</p><p></p

Zebrafish and are paralogous members of the bromodomain-ET (BET) family of transcriptional coregulators that show structural and expression divergence-9

Upported and predicted transcripts from chromosome 16 ENSDARG00000046087 locus from Ensembl and NCBI databases, and D) partial cDNA from NCBI database. Some schematics include 5'UTR and 3' UTR, with wider rectangles depicting protein-coding regions. Boxes show conserved domains: bromodomain (red box); nuclear localization signal (horizontal striped); ET domain (yellow box); in C, degenerate second bromodomain (orange box); in C, upstream TAP domain (light blue box); valine-, leucine-rich region (VL-rich box); arginine-, serine-rich region (RS-rich box); start and stop codons (thick vertical lines); in A, SNPs between zf626 and zf619 (thin vertical lines); in B, discontinuous region in zf69 cDNA with repetitive sequences at bases 921–1033 and 1259–1413 (gray box); conserved intron/exon junction for alternative splicing in -related transcripts (arrow). Two-exon region in cDNA found in scaf_NA1181 is underscored in D. Length of cDNAs in base pairs is given in parentheses.<p><b>Copyright information:</b></p><p>Taken from "Zebrafish and are paralogous members of the bromodomain-ET (BET) family of transcriptional coregulators that show structural and expression divergence"</p><p>http://www.biomedcentral.com/1471-213X/8/39</p><p>BMC Developmental Biology 2008;8():39-39.</p><p>Published online 10 Apr 2008</p><p>PMCID:PMC2373290.</p><p></p

Zebrafish and are paralogous members of the bromodomain-ET (BET) family of transcriptional coregulators that show structural and expression divergence-7

Ral (B) views of whole embryos show expression in all brain subdivisions, especially cerebellum (cb), in neural retina (nr), otic capsule (oc), atrium of heart (h), gill arches (ga), pharynx (ph), swim bladder (sb) and ventral trunk. Cross sections at levels indicated in A reveal expression in: C) amacrine cells (ac) and ganglion cell layer (gcl) of neural retina; D) spinal cord (sc), pronephric duct (pd) and endodermal derivatives such as liver (li); E) posterior lateral line primordium (lat), and endodermal derivatives such as swim bladder and gut (g). expression continues in gut (g), but declines in spinal cord (sc, white) as more posterior sections are assayed (F), and is severely reduced in fin bud (D; fb, white) Expression of (G dorsal, H lateral) is found mainly in head region, but is reduced overall, especially in hindbrain, and nearly absent from otic capsule (oc, white), gill arches (ga, white), heart (h, white), ventral trunk, and endodermal derivatives such as pharanx (ph, white), and swim bladder (sb, white). Bar = 250 μm for A,B,D,G,H; = 100 μm for C,E,F.<p><b>Copyright information:</b></p><p>Taken from "Zebrafish and are paralogous members of the bromodomain-ET (BET) family of transcriptional coregulators that show structural and expression divergence"</p><p>http://www.biomedcentral.com/1471-213X/8/39</p><p>BMC Developmental Biology 2008;8():39-39.</p><p>Published online 10 Apr 2008</p><p>PMCID:PMC2373290.</p><p></p

Zebrafish and are paralogous members of the bromodomain-ET (BET) family of transcriptional coregulators that show structural and expression divergence-6

Ral (B) views of whole embyros show expression abundant in all brain subdivisions and developing pharyngeal arches, and in neural retina (nr), otic vesicle (ov), pectoral fin buds (fb) and ventral trunk. Cross sections at levels indicated in A, reveal expression in: C) mesencephalon (m), diencephalon (d) and neural retina (nr); D) in cells of otic vesicle walls (ov, black arrows); E) in caudal hindbrain (hb), endoderm of prospective digestive tract (en), and pectoral fin bud (fb); F) in developing spinal cord (sc), posterior lateral line primordium (lat), pronephric duct (pn), and endodermal tissue (en), including pancreas progenitor (p) and developing gut (g). Signal in hollow of otic vesicle (white arrows in D) is an artefact due to trapped probe. Although (G dorsal, H lateral) is also expressed in head region and pectoral fin buds (fb), it is reduced in dorsal midbrain, caudal hindbrain, and ventral trunk, and absent from neural retina (nr, white arrow) and otic vesicle (ov, white arrow). Bar = 250 μm for A,B,G,H; = 100 μm for C, D (two right images); = 25 μm for D (left image).<p><b>Copyright information:</b></p><p>Taken from "Zebrafish and are paralogous members of the bromodomain-ET (BET) family of transcriptional coregulators that show structural and expression divergence"</p><p>BMC Developmental Biology 2008;8():39-39.</p><p>Published online 10 Apr 2008</p><p>PMCID:PMC2373290.</p><p></p