ORCID Profile
0000-0001-6626-6897
Current Organisation
Monash University
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Publisher: Cold Spring Harbor Laboratory
Date: 14-04-2014
Abstract: HDAC inhibitors can regulate gene expression by post-translational modification of histone as well as nonhistone proteins. Often studied at single loci, increased histone acetylation is the paradigmatic mechanism of action. However, little is known of the extent of genome-wide changes in cells stimulated by the hydroxamic acids, TSA and SAHA. In this article, we map vascular chromatin modifications including histone H3 acetylation of lysine 9 and 14 (H3K9/14ac) using chromatin immunoprecipitation (ChIP) coupled with massive parallel sequencing (ChIP-seq). Since acetylation-mediated gene expression is often associated with modification of other lysine residues, we also examined H3K4me3 and H3K9me3 as well as changes in CpG methylation (CpG-seq). RNA sequencing indicates the differential expression of ∼30% of genes, with almost equal numbers being up- and down-regulated. We observed broad deacetylation and gene expression changes conferred by TSA and SAHA mediated by the loss of EP300/CREBBP binding at multiple gene promoters. This study provides an important framework for HDAC inhibitor function in vascular biology and a comprehensive description of genome-wide deacetylation by pharmacological HDAC inhibition.
Publisher: BMJ
Date: 04-07-2014
DOI: 10.1136/JMEDGENET-2014-102368
Abstract: Disruption of 11p15 imprinting results in two fetal growth disorders with opposite phenotypes: the Beckwith-Wiedemann (BWS MIM 130650) and the Silver-Russell (SRS MIM 180860) syndromes. DNA methylation defects account for 60% of BWS and SRS cases and, in most cases, occur without any identified mutation in a cis-acting regulatory sequence or a trans-acting factor. We investigated whether 11p15 cis-acting sequence variants account for primary DNA methylation defects in patients with SRS and BWS with loss of DNA methylation at ICR1 and ICR2, respectively. We identified a 4.5 kb haplotype that, upon maternal transmission, is associated with a risk of ICR2 loss of DNA methylation in patients with BWS. This novel region is located within the second intron of the KCNQ1 gene, 170 kb upstream of the ICR2 imprinting centre and encompasses two CTCF binding sites. We showed that, within the 4.5 kb region, two SNPs (rs11823023 and rs179436) affect CTCF occupancy at DNA motifs flanking the CTCF 20 bp core motif. This study shows that genetic variants confer a risk of DNA methylation defect with a parent-of-origin effect and highlights the crucial role of CTCF for the regulation of genomic imprinting of the CDKN1C/KCNQ1 domain.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.NEUBIOREV.2016.06.015
Abstract: The postural tachycardia syndrome (POTS) is characterised clinically by symptoms of light-headedness, palpitations, fatigue and exercise intolerance occurring with standing and relieved by lying down. Symptoms occur in association with an inappropriate rise in heart rate in the absence of a fall in blood pressure with the assumption of standing. The pathophysiology of POTS is complicated and poorly understood. Plasma norepinephrine (NE) is often elevated in patients with POTS, resulting in consideration of dysfunction of the norepinephrine transporter (NET) encoded by SLC6A2 gene. Whilst some studies have implicated a defect in the SLC6A2 gene, the cause of reduced SLC6A2 expression and function remains unclear. The search to explain the molecular mechanism of NET dysfunction has focused on genetic variation in the SLC6A2 gene and remains inconclusive. More recent studies show epigenetic mechanisms implicated in the regulation of SLC6A2 expression. In this article, we discuss the epigenetic mechanisms involved in SLC6A2 repression and highlight the potential therapeutic application of targeting these mechanisms in POTS.
Publisher: The American Association of Immunologists
Date: 10-2028
Abstract: Atherosclerosis is a chronic inflammatory arterial disease characterized by focal accumulation of lipid and inflammatory cells. It is the number one cause of deaths in the Western world because of its complications of heart attacks and strokes. Statins are effective in only approximately one third of patients, underscoring the urgent need for additional therapies. B cells that accumulate in atherosclerotic lesions and the aortic adventitia of humans and mice are considered to protect against atherosclerosis development. Unexpectedly, we found that selective B cell depletion in apolipoprotein E-deficient (ApoE−/−) mice using a well-characterized mAb to mouse CD20 reduced atherosclerosis development and progression without affecting the hyperlipidemia imposed by a high-fat diet. Adoptive transfer of 5 × 106 or 5 × 107 conventional B2 B cells but not 5 × 106 B1 B cells to a lymphocyte-deficient ApoE−/− Rag-2−/− common cytokine receptor γ-chain–deficient mouse that was fed a high-fat diet augmented atherosclerosis by 72%. Transfer of 5 × 106 B2 B cells to an ApoE−/− mouse deficient only in B cells aggravated atherosclerosis by & %. Our findings provide compelling evidence for the hitherto unrecognized proatherogenic role of conventional B2 cells. The data indicate that B2 cells can potently promote atherosclerosis development entirely on their own in the total absence of all other lymphocyte populations. Additionally, these B2 cells can also significantly augment atherosclerosis development in the presence of T cells and all other lymphocyte populations. Our findings raise the prospect of B cell depletion as a therapeutic approach to inhibit atherosclerosis development and progression in humans.
Publisher: Elsevier BV
Date: 07-2015
Publisher: Informa UK Limited
Date: 17-03-2016
DOI: 10.1586/14789450.2016.1159960
Abstract: Many epigenetic-based therapeutics, including drugs such as histone deacetylase inhibitors, are now used in the clinic or are undergoing advanced clinical trials. The study of chromatin-modifying proteins has benefited from the rapid advances in high-throughput sequencing methods, the organized efforts of major consortiums and by in idual groups to profile human epigenomes in erse tissues and cell types. However, while such initiatives have carefully characterized healthy human tissue, disease epigenomes and drug-epigenome interactions remain very poorly understood. Reviewed here is how high-throughput sequencing improves our understanding of chromatin regulator proteins and the potential implications for the study of human disease and drug development and discovery.
Publisher: Springer Science and Business Media LLC
Date: 25-02-2015
Publisher: Springer Science and Business Media LLC
Date: 17-05-2014
DOI: 10.1007/S00018-014-1651-Y
Abstract: Methyl-dependent regulation of transcription has expanded from a traditional focus on histones to encompass transcription factor modulation. While the Set7 lysine methyltransferase is associated with pro-inflammatory gene expression in vascular endothelial cells, genome-wide regulatory roles remain to be investigated. From initial characterization of Set7 as specific for methyl-lysine 4 of H3 histones (H3K4m1), biochemical activity toward non-histone substrates has revealed additional mechanisms of gene regulation. mRNA-Seq revealed transcriptional deregulation of over 8,000 genes in an endothelial model of Set7 knockdown. Gene ontology identified up-regulated pathways involved in developmental processes and extracellular matrix remodeling, whereas pathways regulating the inflammatory response as well as nitric oxide signaling were down-regulated. Chromatin maps derived from ChIP-Seq profiling of H3K4m1 identified several hundred loci with loss of H3K4m1 at gene regulatory elements associated with an unexpectedly subtle effect on gene expression. Transcription factor network analysis implicated six previously described Set7 substrates in mRNA-Seq changes, and we predict that Set7 post-translationally regulates other transcription factors associated with vascular endothelial gene expression through the presence of Set7 amino acid methylation motifs. We describe a role for Set7 in regulating developmental pathways and response to stimuli (inflammation/immune response) in human endothelial cells of vascular origin. Set7-dependent gene expression changes that occurred independent of H3K4m1 may involve transcription factor lysine methylation events. The method of mapping measured transcriptional changes to transcription factors to identify putative substrates with strong associations to functional changes is applicable to substrate prediction for other broad-substrate histone modifiers.
Publisher: Informa UK Limited
Date: 02-12-2017
Publisher: Maad Rayan Publishing Company
Date: 04-10-2021
Abstract: Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) has been recently identified as a novel member of beta coronaviruses (CoVs) and the cause of coronavirus disease-2019 (COVID-19). It has been first discovered in China and soon has spread across continents with an escalating number of mortalities. There is an urgent need for developing a COVID-19 vaccine to control the rapid transmission and the deleterious impact of the virus. The potent vaccine should have a good tolerable and efficacious profile to induce target-specific humoral and cellular immune responses. It should also exhibit no or minimal detrimental effects in children, young adults, and elderly people with or without co-morbidities from different racial backgrounds. Previously published findings of Severe Acute Respiratory Syndrome associated Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) played vital role in the characterization of surface spike proteins as the tool of entry of the SARS-CoV-2 into host cells. It has become evident that SARS-CoVs have high genetic similarity and this implies antecedent vaccination strategies could be implicated in the production of COVID-19 vaccines. Although several vaccines have been approved and rolled out, only a handful of them have passed the three phases of clinical studies. This review highlights the completed, and ongoing clinical trials of COVID-19 vaccines and efforts are being made globally to avert the pandemic.
Publisher: No publisher found
Date: 2010
Publisher: American Medical Association (AMA)
Date: 11-2013
DOI: 10.1001/JAMASURG.2013.3728
Abstract: Pancreas isum is an uncommon congenital anomaly that may result in chronic pancreatitis (chronic pancreatitis secondary to pancreas isum [CPPD]) and intractable pain. We evaluated the role of the Frey procedure in the management of patients with pain related to CPPD as compared with patients with chronic pancreatitis secondary to alcohol (CPA) or idiopathic causes (ICP). To review our experience with the Frey procedure for the management of chronic pancreatitis related to pancreas isum. This was a 2-year institutional retrospective of patients undergoing the Frey procedure for chronic pancreatitis related-pain from April 2008 to June 2010. Academic tertiary care referral center. A consecutive s le of 14 patients undergoing the Frey procedure for chronic pancreatitis and disease-related intractable pain. We sought to examine the utility of the Frey procedure in patients with CPPD as compared with CPA and ICP. The Frey procedure. Perioperative outcomes and postoperative narcotic requirement were compared among patient groups. Fourteen patients underwent the Frey procedure. The etiology of the disease was pancreas isum in 6 patients, alcohol in 5, and idiopathic in 3. The most common indication for surgery was intractable pain, and all patients had undergone endoscopic retrograde cholangiopancreatography for attempted relief in the past. There were no statistically significant differences in median operative time (263 minutes), intraoperative blood loss (425 mL), median length of stay (9.5 days), or rate of morbidity (21%) between the 3 etiologies. Two-thirds of patients required less or no opioid at follow-up, although follow-up was significantly longer for CPPD and ICP than CPA (median, 249, 259, and 42 days, respectively P < .02). In this series, outcomes for patients with CPPD treated with the Frey procedure were equivalent to those treated for CPA. Patients with pancreas isum and a dilated pancreatic duct may be ideally suited for this surgical strategy. The potential advantage of this approach over minor duct sphincteroplasty and lateral pancreaticojejunostomy is the removal of the fibrotic tissue of the head of the pancreas, thought to be the epicenter of pain in this condition. The benefits over resection alone include a more extensive ductal drainage procedure.
Publisher: American Society for Clinical Investigation
Date: 23-03-2017
Publisher: Oxford University Press (OUP)
Date: 16-03-2023
No related grants have been discovered for Abdul Waheed Khan.