decoding-epitranscriptome-silico-insights-into-m6a-regulatory-network

Decoding The Epitranscriptome: <em>In Silico</em> Insights Into m6A Regulatory Network In Breast Cancer

N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic transcripts and plays a critical role in RNA metabolism, gene ...

Alfaisal University

Epidemiological models have been used extensively to predict disease spread in large populations. Among these models, Susceptible Infectious Exposed Recovered (SEIR) is considered to be a suitable model for COVID-19 spread predictions. However, SEIR in its classical form is unable to quantify the impact of lockdowns. In this work, we introduce a variable in the SEIR system of equations to study the impact of various degrees of social distancing on the spread of the disease. As a case study, we apply our modified SEIR model on the initial spread data available (till April 9, 2020) for the Kingdom of Saudi Arabia (KSA). Our analysis shows that with no lockdown around 2.1 million people might get infected during the peak of spread around 2 months from the date the lockdown was first enforced in KSA (March 25th). On the other hand, with the Kingdom's current strategy of partial lockdowns, the predicted number of infections can be lowered to 0.4 million by September 2020. We further demonstrate that with a stricter level of lockdowns, the COVID-19 curve can be effectively flattened in KSA.

Impact of lockdowns on the spread of COVID-19 in Saudi Arabia.

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths worldwide. Prostate tumorigenesis and PCa progression involve numerous genetic as well as epigenetic perturbations. Histone modification represents a fundamental epigenetic mechanism that regulates diverse cellular processes, and H3K4 methylation, one such histone modification associated with active transcription, can be reversed by dedicated histone demethylase KDM5B (JARID1B). Abnormal expression and functions of KDM5B have been implicated in several cancer types including PCa. Consistently, our bioinformatics analysis reveals that the  mRNA levels are upregulated in PCa compared to benign prostate tissues, and correlate with increased tumor grade and poor patient survival, supporting an oncogenic function of KDM5B in PCa. Surprisingly, however, when we generated prostate-specific conditional  knockout mice using probasin (Pb) promoter-driven  system, we observed that  deletion did not affect normal prostate development but instead induced mild hyperplasia. These results suggest that KDM5B may possess context-dependent roles in normal prostate development vs. PCa development and progression.

Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer.

Transport of functional molecules across the nuclear membrane of a eukaryotic cell is regulated by a dedicated set of transporter proteins that carry molecules into the nucleus or out of the nucleus to the cytoplasm for homeostasis of the cell. One of the categories of cargo molecules these transporters carry are the molecules for cell cycle regulation. Therefore, their role is critical in terms of cancer development. Any misregulation of the transport factors would means aberrant abundance of cell cycle regulators and might have consequences in cell cycle progression. While earlier studies have focussed on individual transport related molecules, a collective overview of how these molecules may be dysregulated in breast cancer is lacking. Using genomic and transcriptomic datasets from TCGA (The Cancer Genome Atlas) and microarray platforms, we carried out bioinformatic analysis and provide a genetic and molecular profile of all the molecules directly related to nucleocytoplasmic shuttling of proteins and RNAs. Interestingly, we identified that many of these molecules are either mutated or have dysregulated expression in breast cancer. Strikingly, some of the molecules, namely,  were correlated with poor patient survival. This study provides a comprehensive genetic and molecular landscape of nucleocytoplasmic factors in breast cancer and points to the important roles of various nucleocytoplasmic factors in cancer progression. This data might have implications in prognosis and therapeutic targeting in breast cancer.

Molecular profiling of nucleocytoplasmic transport factor genes in breast cancer.

The nuclear transport of proteins is important for facilitating appropriate nuclear functions. The importin α family proteins play key roles in nuclear transport as transport receptors for copious nuclear proteins. Additionally, these proteins possess other functions, including chromatin association and gene regulation. However, these nontransport functions of importin α are not yet fully understood, especially their molecular-level mechanisms and consequences for functioning with chromatin. Here, we report the novel molecular characteristics of importin α binding to diverse DNA sequences in chromatin. We newly identified and characterized a DNA-binding domain-the Nucleic Acid Associating Trolley pole domain (NAAT domain)-in the N-terminal region of importin α within the conventional importin β binding (IBB) domain that is necessary for nuclear transport of cargo proteins. Furthermore, we found that the DNA binding of importin α synergistically coupled the recruitment of its cargo protein to DNA. This is the first study to delineate the interaction between importin α and chromatin DNA via the NAAT domain, indicating the bifunctionality of the importin α N-terminal region for nuclear transport and chromatin association.

Importin α2 association with chromatin: Direct DNA binding via a novel DNA-binding domain.

COVID-19 has transformed the life of human beings and digital twin infrastructure can facilitates working remotely during COVID-19 outbreak by reducing burden on services and infrastructure. Currently, many organizations are installing and developing devices such as thermal cameras, sensors aiming to minimize human contact and so forth, in addition to enforcing social distancing resulting in reducing the risk of transmission. Due to economic reasons, lockdown restrictions are being relaxed/lifted in many countries and Pakistan which is one of the most densely populated countries in the world with a population of 220 + million is no exception. Though, Pakistan contained the first two waves of coronavirus infections reasonably well but the country is struggling to contain the third wave of the spread due to violations of social distancing norms. While our predictions may deviate from official statistics due to lack of mass testing and existence of asymptomatic infections, the described approach predicts the possible actual burden of infection over times. In view of the unique demographics, our data quantify the efficacy of social distancing as an effective measure to forestall the infection. We highlight few areas where digital twins can be created/deployed to provide services and essential facilities to citizens as COVID-19 is expected to have permanent impact on the way we work.

COVID-19 outbreak and the role of digital twin.

Epigenomic anomalies contribute significantly to the development of numerous human disorders. The development of epigenetic research tools is essential for understanding how epigenetic marks contribute to gene expression. A gene-editing technique known as CRISPR (clustered regularly interspaced short palindromic repeats) typically targets a particular DNA sequence using a guide RNA (gRNA). CRISPR/Cas9 technology has been remodeled for epigenome editing by generating a 'dead' Cas9 protein (dCas9) that lacks nuclease activity and juxtaposing it with an epigenetic effector domain. Based on fusion partners of dCas9, a specific epigenetic state can be achieved. CRISPR-based epigenome editing has widespread application in drug screening, cancer treatment and regenerative medicine. This paper discusses the tools developed for CRISPR-based epigenome editing and their applications.

CRISPR-based epigenome editing: mechanisms and applications.

N6-methyladenosine (m6A) is an RNA modification wherein the N6-position of adenosine is methylated. It is one of the most prevalent internal modifications of RNA and regulates various aspects of RNA metabolism. M6A is deposited by m6A methyltransferases, removed by m6A demethylases, and recognized by reader proteins, which modulate splicing, export, translation, and stability of the modified mRNA. Recent evidence suggests that various classes of non- coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long con-coding RNAs (lncRNAs), are also targeted by this modification. Depending on the ncRNA species, m6A may affect the processing, stability, or localization of these molecules. The m6A- modified ncRNAs are implicated in a number of diseases, including cancer. In this review, the author summarizes the role of mA modification in the regulation and functions of ncRNAs in tumor development. Moreover, the potential applications in cancer prognosis and therapeutics are discussed.

Article	Year
Impact of lockdowns on the spread of COVID-19 in Saudi Arabia. Informatics in medicine unlocked\| PubMed ID: 32905098	2020
Evidence for context-dependent functions of KDM5B in prostate development and prostate cancer. Oncotarget\| PubMed ID: 33245716	2020
Molecular profiling of nucleocytoplasmic transport factor genes in breast cancer. Heliyon\| PubMed ID: 33553736	2021
Importin α2 association with chromatin: Direct DNA binding via a novel DNA-binding domain. Genes to cells : devoted to molecular & cellular mechanisms\| PubMed ID: 34519142	2021
COVID-19 outbreak and the role of digital twin. Multimedia tools and applications\| PubMed ID: 35002471	2022
CRISPR-based epigenome editing: mechanisms and applications. Epigenomics\| PubMed ID: 37990877	2023
Ramifications of m6A Modification on ncRNAs in Cancer. Current genomics\| PubMed ID: 39087001	2024

Rashid Mehmood

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