Dr. Islam has been working at the Department of Genetic Engineering & Biotechnology, University of Dhaka since 2005. However, he also served in the Stamford University Bangladesh (Microbiology) and North South University (Environmental Studies), Oceanography Department of Dhaka University as faculty member. He is also serving as part-time faculty of Pharmacy Department of Dhaka University and in cBLAST of Dhaka University.
Visiting Scientist/Scholar Position
Dr. Islam was awarded with visiting scientist/scholar position in Japan, Spain and USA.
Meeting with Nobel Laureates
Through a national and finally world-wide international competition, Dr. Islam was selected to participate in the 57th Meetings of Nobel Laureates at Lindau, Lake Constance, Germany. This was the first batch to participate in the Nobel Laureates meeting from Bangladesh in 2007.
To participate workshops, conferences and training etc (USA, UK, Australia, Japan, China, Germany, Switzerland, Netherlands, Austria, France, Switzerland, Spain, Italy, Hungary, Belgium, Malta, Romania, Slovenia, Turkey, Tunisia, KSA, Singapore, Malaysia, Bhutan, Vietnam, India) Dr. Islam was awarded with competitive fellowships/travel grants etc.
Research Contribution to Biomedical Sciences
(1) KDM5A links to cancer and epigenetic drug target discovery:
Dr. Abul Bashar Mir Md. Khademul Islam is recognized for his contribution for elucidating the mechanism how precisely cell differentiation is coupled with halted cell cycle progression and the involvement of epigenetic regulations in this process. He explained the role of KDM5A (Histone demethylase) in cancer and proved the concept more effective of combinatorial epigenetic therapy against the KDM5A with another co-regulating epigenetic enzyme. He discovered coregulatory pattern of histone-modifying enzymes in cancer which can be used for better drug design. Also, he uncovered the probable mechanism of aggressive tumor formation by discovering a novel mechanism where the RB/E2F pathway interacts with the Hippo tumor suppressor pathway to synergistically control cell cycle exit upon differentiation. Recently he identified a gene-set responsible for tumor cell migration/progression in colon cancer and showed a way to predict prognosis of this cancer patient. Moreover, he also discovered the novel function of host-gene regulation by its embedded micro-RNA.
Dr. Islam’s work is highly applicable to human health. Epigenetic drug discovery is a relatively new field and as such the effect of epigenetic drugs at level of the whole human genome presents a problem for drug developers. Therefore, providing epigenetic overview of the genome using cutting-age technologies is an essential tool for epigenetic drug discovery. Constellation Pharmaceuticals (Cambridge, USA) is a leading epigenetic drug discovery company. Constellation puts much effort on understanding chromatin biology and was especially interested in a collaborative research project. With this mutual interest, their group provided the access for the Constellation to many of genome-wide data that Dr. Islam generated for histone demethylases. His analyses and communication of its results was vital for the data transfer. He worked closely with the bioinformatics group at Constellation to refine the analysis results that would meet the companies’ goals. Some aspects of knowledge transfer included precise genome locations of sites of binding of epigenetic enzymes. Others included the protocols for data generation and data analysis. In all these, he played a crucial role. The intellectual property of this collaborative project has been highly recognized by the Constellation. As the result of this collaboration, more than ten license agreements were signed on the use of data and associated reagents. The Constellation put forward a research agreement aimed at comprehensive genome-wide analysis using computational tools adopted and refined by Dr. Islam specifically for epigenetic targets. Dr. Islam’s analysis yielded important insights into epigenetic adaptations of cancer cells while confirming their functional significance, and in so doing, helped in providing a basis for the rational epigenetic therapies.
His work mostly focused on histone modifying enzyme KDM5 and its relation to the pRB/E2F tumor suppressor pathway. In these studies, Dr. Islam lent his experience and skills examining the levels of epigenetic enzymes in several human cancers. The inactivation of the retinoblastoma (RB1) gene is viewed as a necessary step in the development of human cancers and KDM5A provides an important mechanistic link to pRB functions in differentiation and cell cycle, which makes KDM5A an important drug target. Dr. Islam identified genome-wide targets of KDM5A and explained the demethylation dependent mechanisms of differentiation and cell regulation.
More recently, he identified expression signatures of genes encoding histone demethylase and methyltransferases that can be used to cancer diagnosis and disease stage classification. His research pointed that a combination therapy which includes KDM5A and other histone modifying enzymes would be more effective and less toxic than single drug therapy. Recently he identified a gene-set responsible for tumor cell migration/progression in colon cancer and showed a way to predict prognosis of this cancer patient. These findings put one step forward in understanding epigenetic mechanisms and cancer drug discovery.
He then has made a step to study a relationship between different tumor suppressor pathways and decided to collaborate with another laboratory in the USA, which used a genetic model, Drosophila, to study cell cycle and differentiation control. His collaboration with this lab led by Dr. Maxim Frolov, resulted in several publications in high profile journals. Dr. Islam uncovered the probable mechanism of aggressive tumor formation by discovering a novel mechanism where the RB/E2F pathway interacts with the Hippo tumor suppressor pathway to synergistically control cell cycle exit upon differentiation. Since pRB pathway is frequently mutated in many human tumors and Hippo has role in organ size control, both mutation might led to more aggressive tumors. Therefore, his research has opened the door to explore mechanisms in cancers.
Moreover, in another project he showed a novel mechanism how embedded microRNA can control its host gene targets in apoptosis control. These results also illustrate that examining an intronic miRNA in the context of its host’s function can be valuable in elucidating the biological function of the miRNA, and provide new information about the regulation of the host gene itself. The significant of this finding is that we can use this to control various diseases and control cellular processes. Result of these projects was published in high impact journal Genes and Development, and PLOS Genetics.
Implications of his studies for general knowledge and human health
i. Cancer evolution is a hallmark of the progression to metastatic disease. Cancer cells have remarkable plasticity. They quickly respond to changes in their environment by switching phenotypes, for example from more differentiated to less differentiated states. Switching phenotypes may be due to epigenetic changes, which would mimic lineage commitment in stem cells during normal development. Most recent studies suggest that epigenetic mechanisms are involved. Studying KDM5A and its cross-talk to equivalent pathways will help to uncover new mechanisms driving tumorigenesis. Mr. Islam's finding that KDM5B is recruited to KDM5A targets in the absence of KDM5A indicates that rationally designed drugs that can inhibit both KDM5A and KDM5B would be more effective than KDM5A suppressors alone.
ii. He identified the expression signatures of HDMs/HMTs in a large number of cancer types and showed that they vary from those in normal cells. Also, multiple correlations occur between HDMs and HMTs. These phenomena can be used for diagnostic purposes and for designing combinational therapies.
iii. Differentiation is controlled by the RB/E2F pathway, which is also a tumor suppressor. Mr. Islam showed that the "switching" comes in to play in cancer cells because epigenetic factors (such as KDM5A) interact with tumor suppressors, (such as pRB). He studied a cell culture-based model where pRB is deleted. He showed that by deletion of KDM5A, expansion of these cells can be prevented through initiation of the differentiation program and apoptosis, when prompted to differentiate. As pRB is deregulated in cancer, his studies suggest that use of KDM5A inhibitors would selectively kill cancer cells, while leaving normal Rb-positive cells intact.
iv. Certain key cancer genes are likely to remain relatively difficult to drug. This is a notable problem for the tumor suppressor genes, in which the gene product is often completely absent. His group previously showed that pRB directly interacts with KDM5A. He reported that they are functionally linked to regulation of cell cycle genes, whose deregulation is a hallmark of cancer. I also he found that in cells which completely lack pRB, deletion of KDM5A changes cancer cell properties. The implication of these results is that in the absence of pRB, KDM5A inhibitors can be designed which will target the pRB-dependent process in cancer. His study I have identified direct genomic targets of KDM5A. He also showed isform specific targets and their specific functions which would help identification of more specific targets.
v. The "re-treatment response" after a “drug holiday” is poor in many patients in many cancer types. Recently a direct link between overexpression of the chromatin-modifier KDM5A in cancer subpopulations and drug tolerance has been established. However, the mechanism of their resistance is yet to be explained. Mr. Islam identified KDM5A-dependent regulatory modules, expression signatures and correlation patterns among various HDMs and HMTs which helped in understanding this process. Also, by knockout of KDM5A he showed biological effects which indicate that restoring KDM5A to its normal suppressed level may better manage resistant populations. Moreover, since KDM5A has been shown to associate with HDAC, it is probable that combination therapy would be more effective against most drug refractory populations.
vi. There are implications for therapeutic development in non-oncologic diseases such as sleep disorders. Recently a demethylase dispensable role of KDM5A has been reported. It was found that depletion or over-expression of KDM5A can alter the circadian rhythm. KDM5A might form a complex in the target gene and facilitate demethylation, or it might recruit another protein which performs that function. He elucidated a genome-wide targets that might also help in understanding KDM5A’s role in other such diseases and aid in better drug design.
(2) Genetic and epigenetic mechanisms of cancers:
Dr. Islam's main interest is to discover mechanisms of cancer development, progression and drug resistance. He is actively working on breast, colon, prostate, cervical cancers. He already has made significant contribution towards the breast and colon cancer mechanisms, diagnosis and drug resistance.
Although most breast tumors initially responsive to endocrine therapies, gradually develop resistance through molecular mechanisms that are not yet fully understood. In a study, Dr. Islam and his collaborators use a well-known model of acquired resistance to aromatase inhibitor (AIs) (that is, MCF7–LTED) to comprehensively analyze the mechanism underpinning adaptation to estrogen deprivation in ERa-positive breast cancer. The novelty of their approach derives from two key characteristics: the description of dynamic genomic, transcriptomic and molecular changes; and the integrative analysis of these biological data levels to delineate the adaptive phenomena. Together, their data suggest a mechanism for acquired resistance that is mostly independent of canonical ERa transcriptional.
In a more recent study, Dr. Islam and collaborators discovered another interesting finding that VAV3 mediates resistance to breast cancer endocrine therapy. Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα ) are among the most effective systemic treatments for ERα -positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Dr. Islam and colleagues identify VAV3 as a critical component in this process. This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.
Also in breast cancer research, this year he was able to map of six somatic linker histone H1 variants in human breast cancer cells to uncover specific features of H1.2.
Metastasis is most complicated problem in cancer. Dr. Islam in a recent study also addressed this problem. The aim of his study was the characterization of how Cancer Associated Fibroblasts (CAFs) from primary human colon tumors promote migration of colon cancer cells. His studies show for the first time the heterogeneity of primary CAFs’ effect on colon cancer cell migration. A CAF gene expression signature able to classify patients with colon cancer into high- and low-risk groups was identified.
All of these findings has helped us to understand cancer progression and disease resistance and hence may help in designing better drugs.
(3) Stem Cell research:
Understanding the cellular and molecular mechanisms involved in HSC development is crucial for multiple therapeutic applications such as generation of HSCs from ESCs or induced pluripotent stem cells. This includes deciphering how endothelial-like cells acquire the hematopoietic fate and how a very restricted population achieves the stemness characteristics instead of just going through the hematopoietic pathway. Hematopoietic stem cell (HSC) specification occurs in the embryonic aorta and requires Notch activation; however, most of the Notch-regulated elements controlling de novo HSC generation are still unknown. Dr. Islam and collaborators very recently identified Cdca7 as a novel Notch transcriptional target involved in hematopoietic stem cell emergence during embryonic development.
In another study (under review in Stem Cell journal) to better understand the process of HSC generation, author studied the transcriptional program which identified a complex genetic network for endothelial-to-hematopoietic transition (EHT) that was poorly understood. Their study identifies a novel function of Jag1 during mammalian embryonic development, which is relevant for the specification and generation of HSCs. They modelled that Jag1 plays dual role in the aortic endothelium, first it contributes to the downregulation of the endothelial signature thus facilitating the EHT transition in the hemogenic endothelium, and second, it participates in the acquisition of the hematopoietic phenotype. This knowledge has great importance for the future design of protocols for in vitro generation of HSCs, which is a relevant issue in regenerative medicine, in particular for producing cells suitable for transplantation in patients without compatible blood donors.
Understanding the complex regulatory signals that govern the generation of HSC is of biological importance and clinical relevance. Thus Dr. Islam and his co-workers study can be viewed as an advancement of stem cell therapy.
(4) Developmental/transdifferentiation biology
Dr. Islam has made considerable contribution in our understanding of B-cells trasdifferentiation mechanisms.
In collaboration with Dr. Maribel Parara (Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute, Spain) uncovered a novel role for HDAC7 in maintaining the identity of a particular cell type by silencing lineage inappropriate genes. They examined the molecular mechanism responsible for the gene silencing of lineage undesirable genes in B cell precursors and uncovered the role played in this process by the histone deacetylase HDAC7. Therefore Dr. Islam's group identified a novel lineage-specific transcriptional repressor in the hematopoietic system.
In another line of research with Dr. Esteban Ballestar, Dr. Islam investigated the potential participation of chromatin mechanisms during the EBV-mediated transformation of resting B cells (RBL). In this study, Dr. Islam investigated global changes in histone modifications as well as accessibility to endonucleases during the EBV-mediated transformation of RBLs to proliferative lymphoblasts. This study has led to identification of a novel phenomenon implicating global chromatin changes related to EBV-mediated transformation of B cells. His analysis of a related mechanism stimulating B cell proliferation, together with the analysis of the effects of recombinant EBV forms, highlights the association of these changes with growth transformation but not with the pure acquisition of proliferation capabilities.
In another research in collaboration of the same group, Dr. Islam observed that the B cell transcription program mediates hypomethylation and overexpression of key genes in Epstein-Barr virus-associated proliferative conversion. His findings provided novel clues on the role of the B cell transcription program leading to DNA methylation changes, which are found to be key to the EBV-associated conversion of resting B cells to proliferating lymphoblasts. These findings highlight the relevance of potential early mechanisms in this group of tumors.
(5) Drug and vaccine design against life threatening microbes
One line of Dr. Islam's research is in silico modeling of vaccine and drug against bacteria and viruses as well as drug screening against arthritis and cancer gene targets. His team is working on the designing of effective small molecules against Streptococcus extracellular protease SepM, and structure based model of small molecule against Vibrio cholerae toxin-antitoxin system.
Human coronaviruses have recently emerged, includes SARS-CoV and the recent infection by deadly MERS-CoV, now going to cause another outbreak. Prevention of these viruses is urgent and a universal vaccine for all strain could be a promising solution in this circumstance. To solve this problem, Dr. Islam has come forward and designed an epitope based universal vaccine which can be used to prevent all kind of human coronaviruses. This result has published in BMC Bioinformatics journal which has gained highly access status.
Previously he worked with Japanese group and made important contribution on molecular epidemiology of adenovirus infection among infants and children with acute gastroenteritis in Dhaka city, Bangladesh, and epidemiological and molecular analysis of astrovirus gastroenteritis in Dhaka city, Bangladesh
(6) Discoveries in arthritis research
Dr. Islam and co-workers are working on the understanding of the arthritis disease mechanism and biomarker discovery. Some papers have been published already which includes Genome Biology, Genomics Proteomics & Bioinformatics and DNA and Cell Biology. Also two other papers are about to out soon.
Dr. Islam contributes to identify of novel markers in rheumatoid arthritis through integrated analysis of DNA methylation and microRNA expression. This study enabled the identification of novel dysregulated targets in rheumatoid arthritis synovial fibroblasts and generated a new workflow for the integrated analysis of miRNA and other epigenetic control. His study significantly contributed to the development of arthritis diagnosis and led to the identification of new targets including epigenetic targets.
His recent observations (published in DNA and Cell biology) bolster the complex role of these alarmins, DAMPs, and HMGs as innate and endogenous regulators of injury-induced sterile inflammation in the cartilage and joints, their collaborative role in chondrogenesis, hypertrophy, and maintenance of the homeostasis in mice and human cartilage. There is significant focus on the therapeutic intervention of HMGB1. Current findings of Dr. Islam and associates have put one step ahead in the development of more effective drugs.
While studying with Arthritis patients genome-wide expression data, Dr. Islam surprisingly has found an interesting cancer gene signature in osteoarthritis. This manuscript is now under review. These studies show the novel functional role of MIF-COX-p53 axis in sterile inflammation and neuronal/brain tumors at the genomic and proteomics level. He is also working to design drug targets against MIF target.
(7) Contribution in Coronavirus Research
Dr. Islam and his team started research on coronavirus in 2013. His team showed that RNA directed RNA polymerase of human coronaviruses can be used as epitope-based universal vaccine design. Also, conserved antigenic sites between MERS-CoV and Bat-coronavirus are revealed through sequence analysis by this team. During current pandemic situation, his specially selected team members (nCoV research team) started to dig deep into the genome and transcriptome of SARS-CoV-2 & human hosts respectively. They have identified the host-pathogen interaction models. He has identified the key genes and pathways deregulated due to SRAS-CoV-2 infections. His team also found the mechanism of lung damage and proposed surfactant therapy. Moreover, they have revealed the role of epigenetic miRNA/lincRNA from both host and virus.
Dr. Islam contributed to the development of ‘IntOGen’ (www.intogen.org) - a novel and innovative discovery system for oncology research. This system was published in very prestigious Nature method journal. He also contributed to the development of a popular bioinformatic tools Gitools (www.gitools.org) – a method for multi-dimensional data analysis and visualization. He is working on the development of algorithm called ‘ASSBD’ - A Novel and Automated System for Structural Break Detection in DNA Sequences.
He is actively providing training on Bioinformatics/Computational Biology/Systems Biology to the students and researchers through workshop, seminar and training programs throughout the country and abroad regularly. He is also General Secretary (interim committee) of Bangladesh Society for Bioinformatics.
With Prof. Dr. Zeba Islam Seraj of the Department of Biochemistry and Molecular Biology, University of Dhaka, Dr. Islam pioneered in the development of first online Bioinformatic learning initiatives called “Center for Bioinformatics Learning Advancement and Systematics Training (cBLAST)” as a non-profit center under the Dhaka University. This is the first online Bioinformatic learning center in Bangladesh for bioinformatics.
Collaboration in research
Due to his research in modern field of epigenetics, oncogenomics, bioinformatics and due to his achievements in research, several foreign scientists, including some leading scientists in these fields, have shown their interest to work with him and there are several scientists actively doing collaborative projects with him. This includes scientists from Spain, USA, Canada and India. He has also made collaborations with national scientists and clinicians from Bangabandhu Sheikh Mujib Medical University Hospital (BSMMU), National Institute of Cancer Research & Hospital (NICRH), and Ibrahim Medical College (BIRDEM) for research on cancer patients and diabetic patients. Also, he has collaboration with scientist from Chittagong University, Bangladesh Jute Genome Research Institute (BJRI), Chittagong Veterinary and Animal Sciences University (CVASU) to work on high throughput genome sequencing projects and SARS-CoV-2 projects. This way he has several collaborations active to work on complicated projects and projects of national and international interests in the field of biomedical sciences.