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Article ; Online: Minor Intron Splicing from Basic Science to Disease.

El Marabti, Ettaib / Malek, Joel / Younis, Ihab

International journal of molecular sciences

2021 Volume 22, Issue 11

Abstract: Pre-mRNA splicing is an essential step in gene expression and is catalyzed by two machineries in eukaryotes: the major (U2 type) and minor (U12 type) spliceosomes. While the majority of introns in humans are U2 type, less than 0.4% are U12 type, also ... ...

Abstract	Pre-mRNA splicing is an essential step in gene expression and is catalyzed by two machineries in eukaryotes: the major (U2 type) and minor (U12 type) spliceosomes. While the majority of introns in humans are U2 type, less than 0.4% are U12 type, also known as minor introns (mi-INTs), and require a specialized spliceosome composed of U11, U12, U4atac, U5, and U6atac snRNPs. The high evolutionary conservation and apparent splicing inefficiency of U12 introns have set them apart from their major counterparts and led to speculations on the purpose for their existence. However, recent studies challenged the simple concept of mi-INTs splicing inefficiency due to low abundance of their spliceosome and confirmed their regulatory role in alternative splicing, significantly impacting the expression of their host genes. Additionally, a growing list of minor spliceosome-associated diseases with tissue-specific pathologies affirmed the importance of minor splicing as a key regulatory pathway, which when deregulated could lead to tissue-specific pathologies due to specific alterations in the expression of some minor-intron-containing genes. Consequently, uncovering how mi-INTs splicing is regulated in a tissue-specific manner would allow for better understanding of disease pathogenesis and pave the way for novel therapies, which we highlight in this review.
MeSH term(s)	Animals ; Disease/genetics ; Evolution, Molecular ; Humans ; Introns/genetics ; Organ Specificity/genetics ; RNA Splicing/genetics ; Spliceosomes/metabolism
Language	English
Publishing date	2021-06-04
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22116062
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Article: Identifying novel interactions of the colon-cancer related APC protein with Wnt-pathway nuclear transcription factors.

Al-Thani, Nayra M / Schaefer-Ramadan, Stephanie / Aleksic, Jovana / Mohamoud, Yasmin A / Malek, Joel A

Cancer cell international

2022 Volume 22, Issue 1, Page(s) 376

Abstract: Background: Colon cancer is often driven by mutations of the adenomatous polyposis coli (APC) gene, an essential tumor suppressor gene of the Wnt β-catenin signaling pathway. APC and its cytoplasmic interactions have been well studied. However, various ... ...

Abstract	Background: Colon cancer is often driven by mutations of the adenomatous polyposis coli (APC) gene, an essential tumor suppressor gene of the Wnt β-catenin signaling pathway. APC and its cytoplasmic interactions have been well studied. However, various groups have also observed its presence in the nucleus. Identifying novel interactions of APC in the Wnt pathway will provide an opportunity to understand APC's nuclear role better and ultimately identify potential cancer treatment targets. Methods: We used the all-vs-all sequencing (AVA-Seq) method to interrogate the interactome of protein fragments spanning most of the 60 Wnt β-catenin pathway proteins. Using protein fragments identified the interacting regions between the proteins with more resolution than a full-length protein approach. Pull-down assays were used to validate a subset of these interactions. Results: 74 known and 703 novel Wnt β-catenin pathway protein-protein interactions were recovered in this study. There were 8 known and 31 novel APC protein-protein interactions. Novel interactions of APC and nuclear transcription factors TCF7, JUN, FOSL1, and SOX17 were particularly interesting and confirmed in validation assays. Conclusion: Based on our findings of novel interactions between APC and transcription factors and previous evidence of APC localizing to the nucleus, we suggest APC may compete and repress CTNNB1. This would occur through APC binding to the transcription factors (JUN, FOSL1, TCF7) to regulate the Wnt signaling pathway including through enhanced marking of CTNNB1 for degradation in the nucleus by APC binding with SOX17. Additional novel Wnt β-catenin pathway protein-protein interactions from this study could lead researchers to novel drug designs for cancer.
Language	English
Publishing date	2022-12-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2091573-1
ISSN	1475-2867
ISSN	1475-2867
DOI	10.1186/s12935-022-02799-1
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Article ; Online: Novel protein contact points among TP53 and minichromosome maintenance complex proteins 2, 3, and 5.

Schaefer-Ramadan, Stephanie / Aleksic, Jovana / Al-Thani, Nayra M / Malek, Joel A

Cancer medicine

2022 Volume 11, Issue 24, Page(s) 4989–5000

Abstract: Objective: Identify protein contact points between TP53 and minichromosome maintenance (MCM) complex proteins 2, 3, and 5 with high resolution allowing for potential novel Cancer drug design.: Methods: A next-generation sequencing-based protein- ... ...

Abstract	Objective: Identify protein contact points between TP53 and minichromosome maintenance (MCM) complex proteins 2, 3, and 5 with high resolution allowing for potential novel Cancer drug design. Methods: A next-generation sequencing-based protein-protein interaction method developed in our laboratory called AVA-Seq was applied to a gold-standard human protein interaction set. Proteins including TP53, MCM2, MCM3, MCM5, HSP90AA1, PCNA, NOD1, and others were sheared and ligated into the AVA-Seq system. Protein-protein interactions were then identified in both mild and stringent selective conditions. Results: Known interactions among MCM2, MCM3, and MCM5 were identified with the AVA-Seq system. The interacting regions detected between these three proteins overlap with the structural data of the MCM complex, and novel domains were identified with high resolution determined by multiple overlapping fragments. Fragments of wild type TP53 were shown to interact with MCM2, MCM3, and MCM5, and details on the location of the interactions were provided. Finally, a mini-network of known and novel cancer protein interactions was provided, which could have implications for fundamental changes in multiple cancers. Conclusion: We provide a high-resolution mini-interactome that could direct novel drug targets and implicate possible effects of specific cancer mutations.
MeSH term(s)	Humans ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/genetics ; Tumor Suppressor Protein p53/chemistry ; Tumor Suppressor Protein p53/genetics ; Minichromosome Maintenance Proteins/classification ; Minichromosome Maintenance Proteins/genetics ; Neoplasms ; Drug Design
Chemical Substances	DNA-Binding Proteins ; TP53 protein, human ; Tumor Suppressor Protein p53 ; Minichromosome Maintenance Proteins (EC 3.6.4.12)
Language	English
Publishing date	2022-05-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2659751-2
ISSN	2045-7634 ; 2045-7634
ISSN (online)	2045-7634
ISSN	2045-7634
DOI	10.1002/cam4.4805
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Article ; Online: Genome-wide association of dry (Tamar) date palm fruit color.

Younuskunju, Shameem / Mohamoud, Yasmin A / Mathew, Lisa S / Mayer, Klaus F X / Suhre, Karsten / Malek, Joel A

The plant genome

2023 Volume 16, Issue 4, Page(s) e20373

Abstract: Date palm (Phoenix dactylifera) fruit (dates) are an economically and culturally significant crop in the Middle East and North Africa. There are hundreds of different commercial cultivars producing dates with distinctive shapes, colors, and sizes. ... ...

Abstract	Date palm (Phoenix dactylifera) fruit (dates) are an economically and culturally significant crop in the Middle East and North Africa. There are hundreds of different commercial cultivars producing dates with distinctive shapes, colors, and sizes. Genetic studies of some date palm traits have been performed, including sex determination, sugar content, and fresh fruit color. In this study, we used genome sequences and image data of 199 dry dates (Tamar) collected from 14 countries to identify genetic loci associated with the color of this fruit stage. Here, we find loci across multiple linkage groups (LG) associated with dry fruit color phenotype. We recover both the previously identified VIRESCENS (VIR) genotype associated with fresh fruit yellow or red color and new associations with the lightness and darkness of dry fruit. This study will add resolution to our understanding of date color phenotype, especially at the most commercially important Tamar stage.
MeSH term(s)	Phoeniceae/genetics ; Genome-Wide Association Study ; Genotype ; Phenotype
Language	English
Publishing date	2023-08-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2375444-8
ISSN	1940-3372 ; 0011-183X
ISSN (online)	1940-3372
ISSN	0011-183X
DOI	10.1002/tpg2.20373
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Article: Evidence of Recombination Suppression Blocks on the Y Chromosome of Date Palm (

Torres, Maria F / Mohamoud, Yasmin A / Younuskunju, Shameem / Suhre, Karsten / Malek, Joel A

Frontiers in plant science

2021 Volume 12, Page(s) 634901

Abstract: ... The ... ...

Abstract	The genus
Language	English
Publishing date	2021-04-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2711035-7
ISSN	1664-462X
ISSN	1664-462X
DOI	10.3389/fpls.2021.634901
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Article ; Online: DNA methylation predicts the outcome of COVID-19 patients with acute respiratory distress syndrome.

Bradic, Martina / Taleb, Sarah / Thomas, Binitha / Chidiac, Omar / Robay, Amal / Hassan, Nessiya / Malek, Joel / Ait Hssain, Ali / Abi Khalil, Charbel

Journal of translational medicine

2022 Volume 20, Issue 1, Page(s) 526

Abstract: Background: COVID-19 infections could be complicated by acute respiratory distress syndrome (ARDS), increasing mortality risk. We sought to assess the methylome of peripheral blood mononuclear cells in COVID-19 with ARDS.: Methods: We recruited 100 ... ...

Abstract	Background: COVID-19 infections could be complicated by acute respiratory distress syndrome (ARDS), increasing mortality risk. We sought to assess the methylome of peripheral blood mononuclear cells in COVID-19 with ARDS. Methods: We recruited 100 COVID-19 patients with ARDS under mechanical ventilation and 33 non-COVID-19 controls between April and July 2020. COVID-19 patients were followed at four time points for 60 days. DNA methylation and immune cell populations were measured at each time point. A multivariate cox proportional risk regression analysis was conducted to identify predictive signatures according to survival. Results: The comparison of COVID-19 to controls at inclusion revealed the presence of a 14.4% difference in promoter-associated CpGs in genes that control immune-related pathways such as interferon-gamma and interferon-alpha responses. On day 60, 24% of patients died. The inter-comparison of baseline DNA methylation to the last recorded time point in both COVID-19 groups or the intra-comparison between inclusion and the end of follow-up in every group showed that most changes occurred as the disease progressed, mainly in the AIM gene, which is associated with an intensified immune response in those who recovered. The multivariate Cox proportional risk regression analysis showed that higher methylation of the "Apoptotic execution Pathway" genes (ROC1, ZNF789, and H1F0) at inclusion increases mortality risk by over twofold. Conclusion: We observed an epigenetic signature of immune-related genes in COVID-19 patients with ARDS. Further, Hypermethylation of the apoptotic execution pathway genes predicts the outcome. Trial registration: IMRPOVIE study, NCT04473131.
MeSH term(s)	Humans ; COVID-19/complications ; COVID-19/genetics ; DNA Methylation/genetics ; Leukocytes, Mononuclear ; Respiration, Artificial ; Respiratory Distress Syndrome/complications ; Respiratory Distress Syndrome/genetics ; SARS-CoV-2
Language	English
Publishing date	2022-11-12
Publishing country	England
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-022-03737-5
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Article ; Online: Discovery of new therapeutic targets in ovarian cancer through identifying significantly non-mutated genes.

Al-Farsi, Halema / Al-Azwani, Iman / Malek, Joel A / Chouchane, Lotfi / Rafii, Arash / Halabi, Najeeb M

Journal of translational medicine

2022 Volume 20, Issue 1, Page(s) 244

Abstract: Background: Mutated and non-mutated genes interact to drive cancer growth and metastasis. While research has focused on understanding the impact of mutated genes on cancer biology, understanding non-mutated genes that are essential to tumor development ... ...

Abstract	Background: Mutated and non-mutated genes interact to drive cancer growth and metastasis. While research has focused on understanding the impact of mutated genes on cancer biology, understanding non-mutated genes that are essential to tumor development could lead to new therapeutic strategies. The recent advent of high-throughput whole genome sequencing being applied to many different samples has made it possible to calculate if genes are significantly non-mutated in a specific cancer patient cohort. Methods: We carried out random mutagenesis simulations of the human genome approximating the regions sequenced in the publicly available Cancer Growth Atlas Project for ovarian cancer (TCGA-OV). Simulated mutations were compared to the observed mutations in the TCGA-OV cohort and genes with the largest deviations from simulation were identified. Pathway analysis was performed on the non-mutated genes to better understand their biological function. We then compared gene expression, methylation and copy number distributions of non-mutated and mutated genes in cell lines and patient data from the TCGA-OV project. To directly test if non-mutated genes can affect cell proliferation, we carried out proof-of-concept RNAi silencing experiments of a panel of nine selected non-mutated genes in three ovarian cancer cell lines and one primary ovarian epithelial cell line. Results: We identified a set of genes that were mutated less than expected (non-mutated genes) and mutated more than expected (mutated genes). Pathway analysis revealed that non-mutated genes interact in cancer associated pathways. We found that non-mutated genes are expressed significantly more than mutated genes while also having lower methylation and higher copy number states indicating that they could be functionally important. RNAi silencing of the panel of non-mutated genes resulted in a greater significant reduction of cell viability in the cancer cell lines than in the non-cancer cell line. Finally, as a test case, silencing ANKLE2, a significantly non-mutated gene, affected the morphology, reduced migration, and increased the chemotherapeutic response of SKOV3 cells. Conclusion: We show that we can identify significantly non-mutated genes in a large ovarian cancer cohort that are well-expressed in patient and cell line data and whose RNAi-induced silencing reduces viability in three ovarian cancer cell lines. Targeting non-mutated genes that are important for tumor growth and metastasis is a promising approach to expand cancer therapeutic options.
MeSH term(s)	Base Sequence ; Carcinoma, Ovarian Epithelial/genetics ; Female ; Genome ; Humans ; Mutation/genetics ; Ovarian Neoplasms/genetics
Language	English
Publishing date	2022-05-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-022-03440-5
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Article ; Online: Identification of human genetic variants controlling circular RNA expression.

Ahmed, Ikhlak / Karedath, Thasni / Al-Dasim, Fatima M / Malek, Joel A

RNA (New York, N.Y.)

2019 Volume 25, Issue 12, Page(s) 1765–1778

Abstract: Circular RNAs (circRNAs) are abundant in eukaryotic transcriptomes and have been linked to various human disorders. However, understanding genetic control of circular RNA expression is in the early stages. Here we present the first integrated analysis of ...

Abstract	Circular RNAs (circRNAs) are abundant in eukaryotic transcriptomes and have been linked to various human disorders. However, understanding genetic control of circular RNA expression is in the early stages. Here we present the first integrated analysis of circRNAs and genome sequence variation from lymphoblastoid cell lines of the 1000 Genomes Project. We identified thousands of circRNAs in the RNA-seq data and show their association with local single-nucleotide polymorphic sites, referred to as circQTLs, which influence the circRNA transcript abundance. Strikingly, we found that circQTLs exist independently of eQTLs with most circQTLs having no effect on mRNA expression. Only a fraction of the polymorphic sites are shared and linked to both circRNA and mRNA expression with mostly similar effects on circular and linear RNA. A shared intronic QTL, rs55928920, of HMSD gene drives the circular and linear expression in opposite directions, potentially modulating circRNA levels at the expense of mRNA. Finally, circQTLs and eQTLs are largely independent and exist in separate linkage disequilibrium (LD) blocks with circQTLs highly enriched for functional genomic elements and regulatory regions. This study reveals a previously uncharacterized role of DNA sequence variation in human circular RNA regulation.
MeSH term(s)	Gene Expression Profiling ; Gene Expression Regulation ; Gene Regulatory Networks ; Genetic Variation ; Genome, Human ; High-Throughput Nucleotide Sequencing ; Humans ; MicroRNAs/genetics ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; RNA, Circular ; RNA, Messenger/genetics ; Sequence Analysis, DNA ; Transcriptome
Chemical Substances	MicroRNAs ; RNA, Circular ; RNA, Messenger
Language	English
Publishing date	2019-09-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.071654.119
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Article ; Online: Deletion of beta-fructofuranosidase (invertase) genes is associated with sucrose content in Date Palm fruit.

Malek, Joel A / Mathew, Sweety / Mathew, Lisa S / Younuskunju, Shameem / Mohamoud, Yasmin A / Suhre, Karsten

Plant direct

2020 Volume 4, Issue 5, Page(s) e00214

Abstract: The fruit of date palm trees are an important part of the diet for a large portion of the Middle East and North Africa. The fruit is consumed both fresh and dry and can be stored dry for extended periods of time. Date fruits vary significantly across ... ...

Abstract	The fruit of date palm trees are an important part of the diet for a large portion of the Middle East and North Africa. The fruit is consumed both fresh and dry and can be stored dry for extended periods of time. Date fruits vary significantly across hundreds of cultivars identified in the main regions of cultivation. Most dried date fruit are low in sucrose but high in glucose and fructose. However, high sucrose content is a distinctive feature of some date fruit and affects flavor as well as texture and water retention. To identify the genes controlling high sucrose content, we analyzed date fruit metabolomics for association with genotype data from 120 date fruits. We found significant association of dried date sucrose content and a genomic region that contains 3 tandem copies of the beta-fructofuranosidase (invertase) gene in the reference Khalas genome, a low-sucrose fruit. High-sucrose cultivars including the popular Deglet Noor had a homozygous deletion of two of the 3 copies of the invertase gene. We show the deletion allele is derived when compared to the ancestral allele that retains all copies of the gene in 3 other species of
Language	English
Publishing date	2020-05-27
Publishing country	England
Document type	Journal Article
ISSN	2475-4455
ISSN (online)	2475-4455
DOI	10.1002/pld3.214
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Article ; Online: Retinal nerve fibre layer thinning and corneal nerve loss in patients with Bardet-Biedl syndrome.

Belkadi, Aziz / Thareja, Gaurav / Khan, Adnan / Stephan, Nisha / Zaghlool, Shaza / Halama, Anna / Ahmed, Ayeda Abdulsalam / Mohamoud, Yasmin A / Malek, Joel / Suhre, Karsten / Malik, Rayaz A

BMC medical genomics

2023 Volume 16, Issue 1, Page(s) 301

Abstract: Background: Bardet-Biedl syndrome (BBS) is an autosomal recessive, genetically heterogeneous, pleiotropic disorder caused by variants in genes involved in the function of the primary cilium. We have harnessed genomics to identify BBS and ophthalmic ... ...

Abstract	Background: Bardet-Biedl syndrome (BBS) is an autosomal recessive, genetically heterogeneous, pleiotropic disorder caused by variants in genes involved in the function of the primary cilium. We have harnessed genomics to identify BBS and ophthalmic technologies to describe novel features of BBS. Case presentation: A patient with an unclear diagnosis of syndromic type 2 diabetes mellitus, another affected sibling and unaffected siblings and parents were sequenced using DNA extracted from saliva samples. Corneal confocal microscopy (CCM) and retinal spectral domain optical coherence tomography (SD-OCT) were used to identify novel ophthalmic features in these patients. The two affected individuals had a homozygous variant in C8orf37 (p.Trp185). SD-OCT and CCM demonstrated a marked and patchy reduction in the retinal nerve fiber layer thickness and loss of corneal nerve fibers, respectively. Conclusion:* This report highlights the use of ophthalmic imaging to identify novel retinal and corneal abnormalities that extend the phenotype of BBS in a patient with syndromic type 2 diabetes.
MeSH term(s)	Humans ; Bardet-Biedl Syndrome/complications ; Bardet-Biedl Syndrome/genetics ; Bardet-Biedl Syndrome/diagnosis ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/genetics ; Retina ; Phenotype ; Nerve Fibers ; Mutation ; Proteins/genetics
Chemical Substances	C8orf37 protein, human ; Proteins
Language	English
Publishing date	2023-11-23
Publishing country	England
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2411865-5
ISSN	1755-8794 ; 1755-8794
ISSN (online)	1755-8794
ISSN	1755-8794
DOI	10.1186/s12920-023-01739-w
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