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Genetics Faculty


Ahmad Khalil
Assistant Professor
Ph.D. Training Faculty
Department of Genetics
School of Medicine
Case Western Reserve University
Biomedical Research Building 620
2109 Adelbert Road
Cleveland, Ohio 44106-4955
Tel: (216) 368-0710
Fax: (216) 368-2010
E-mail: ahmad.khalil@case.edu
https://cancerepigenetics.net/


About Ahmad Khalil

Ahmad Khalil earned his PhD at the University of Florida School of Medicine. His graduate studies focused on elucidating key epigenetic mechanisms that regulate gene expression during mammalian meiosis. Subsequently, he joined the Scripps Research Institute as a postdoctoral fellow (2006-2008) and studied the role of long non-coding RNAs in neurological disorders. In 2008, Dr Khalil moved to Harvard Medical School and the Broad Institute where he played a key role in discovering long intergenic non-coding (linc)RNAs in human cells, and demonstrated that lincRNAs play critical roles in epigenetic regulation of gene expression. In late 2010, Dr Khalil joined the faculty at CWRU and his lab studies the role of lincRNAs and mRNAs in human health and disease. Dr Khalil's laboratory has made several key discoveries including the identification of new genes and pathways that impact the progression of human cancers and drug-resistance. His innovative work is leading to the development of novel therapeutic strategies.


Research

Epigenetic Regulation by Large Intervening Non-coding (linc)RNA

One of the most fundamental and unsolved problems in biology is: how does the same genome present in every cell of an organism encode a multitude of different cellular states? While epigenetic regulation by chromatin-modifying complexes plays a key role in this process, it is not currently known how these complexes are targeted to specific regions of the genome. We hypothesized that lincRNAs may guide chromatin-modifying complexes to specific genomic loci. Using state of the art genomic technologies we demonstrated that numerous lincRNAs associate with chromatin-modifying complexes in several human cell types (Khalil et al., 2009). Through loss-of-function experiments, we found that this subset of lincRNAs is required for proper expression of specific regions of the genome, which are known to be regulated by their associated chromatin-modifying complexes (Khalil et al., 2009).

These studies suggested that lincRNAs play a critical role in regulating gene expression, and may play critical roles in human biology. Indeed, lincRNAs have been, thus far, implicated in dosage compensation, genomic imprinting, alternative splicing of pre-mRNAs, nuclear organization and nuclear-cytoplasmic trafficking (Moran et al., 2012). Also, the dysregulation of lincRNAs have been observed in many human diseases and disorders including cancer and neurological disorders, suggesting that lincRNAs could be utilized as biomarkers or drug targets (Niland et al., 2012, Forrest and Khalil, 2017). My lab is currently focusing on elucidating the mechanisms by which lincRNAs exert their effects, and how to target these novel genes in treatments of human disease.


Selected Publications

The DNMT1-associated lincRNA DACOR1 reprograms genome-wide DNA methylation in colon cancer.
Somasundaram S, Forrest ME, Moinova H, Cohen A, Varadan V, LaFramboise T, Markowitz S, Khalil AM
Clin Epigenetics (2018);10(1):127
See PubMed abstract

Analysis of -5p and -3p Strands of miR-145 and miR-140 During Mesenchymal Stem Cell Chondrogenic Differentiation.
Kenyon JD, Sergeeva O, Somoza RA, Li M, Caplan AI, Khalil AM, Lee Z
Tissue Eng Part A (2018);:
See PubMed abstract

Colon Cancer-Upregulated Long Non-Coding RNA lincDUSP Regulates Cell Cycle Genes and Potentiates Resistance to Apoptosis.
Forrest ME, Saiakhova A, Beard L, Buchner DA, Scacheri PC, LaFramboise T, Markowitz S, Khalil AM
Sci Rep (2018);8(1):7324
See PubMed abstract

Dynamic expression of long noncoding RNAs reveals their potential roles in spermatogenesis and fertility.
Wichman L, Somasundaram S, Breindel C, Valerio DM, McCarrey JR, Hodges CA, Khalil AM
Biol Reprod (2017);97(2):313-323
See PubMed abstract

Review: Regulation of the Cancer Epigenome by Long Non-coding RNAs.
Forrest ME, Khalil AM
Cancer Lett (2017);:
See PubMed abstract

Wnt/β-catenin Signaling Pathway Regulates Specific lncRNAs That Impact Dermal Fibroblasts and Skin Fibrosis.
Mullin NK, Mallipeddi NV, Hamburg-Shields E, Ibarra B, Khalil AM, Atit RP
Front Genet (2017);8:183
See PubMed abstract

S-Nitrosoglutathione Attenuates Airway Hyperresponsiveness in Murine Bronchopulmonary Dysplasia.
Raffay TM, Dylag AM, Di Fiore JM, Smith LA, Einisman HJ, Li Y, Lakner MM, Khalil AM, MacFarlane PM, Martin RJ, Gaston B
Mol Pharmacol (2016);90(4):418-26
See PubMed abstract

Regulation of paxillin-p130-PI3K-AKT signaling axis by Src and PTPRT impacts colon tumorigenesis.
Zhao Y, Scott A, Zhang P, Hao Y, Feng X, Somasundaram S, Khalil AM, Willis J, Wang Z
Oncotarget (2016);:
See PubMed abstract

Transcriptome-wide identification of mRNAs and lincRNAs associated with trastuzumab-resistance in HER2-positive breast cancer.
Merry CR, McMahon S, Forrest ME, Bartels CF, Saiakhova A, Bartel CA, Scacheri PC, Thompson CL, Jackson MW, Harris LN, Khalil AM
Oncotarget (2016);:
See PubMed abstract

DNMT1-associated long non-coding RNAs regulate global gene expression and DNA methylation in colon cancer.
Merry CR, Forrest ME, Sabers JN, Beard L, Gao XH, Hatzoglou M, Jackson MW, Wang Z, Markowitz S, Khalil AM
Hum Mol Genet (2015);:
See PubMed abstract

Integrative transcriptome-wide analyses reveal critical HER2-regulated mRNAs and lincRNAs in HER2+ breast cancer.
Merry CR, McMahon S, Thompson CL, Miskimen KL, Harris LN, Khalil AM
Breast Cancer Res Treat (2015);:
See PubMed abstract

Identification of mRNAs and lincRNAs associated with lung cancer progression using next-generation RNA sequencing from laser micro-dissected archival FFPE tissue specimens.
Morton ML, Bai X, Merry CR, Linden PA, Khalil AM, Leidner RS, Thompson CL
Lung Cancer (2014);:
See PubMed abstract

The functional characterization of the long noncoding RNA SPRY4-IT1 in human melanoma cells.
Mazar J, Zhao W, Khalil AM, Lee B, Shelley J, Govindarajan S, Yamamoto F, Ratnam M, Aftab MN, Collins S, Finck BN, Han X, Mattick JS, Dinger ME, Perera RJ
Oncotarget (2014);

Evolutionarily conserved long intergenic non-coding RNAs in the eye.
Mustafi D, Kevany BM, Bai X, Maeda T, Sears JE, Khalil AM, Palczewski K
Hum Mol Genet (2013);:
See PubMed abstract

Chromatin regulation by long non-coding RNAs
Factor D, Tesar PJ, Khalil AM
Book title: Molecular Biology of Long Non-coding RNAs. (2013);Springer, 2013 Edition

Emerging functional and mechanistic paradigms of mammalian long non-coding RNAs.
Moran VA, Perera RJ, Khalil AM
Nucleic Acids Res (2012);40(14):6391-400
See PubMed abstract

Decapping of long noncoding RNAs regulates inducible genes.
Geisler S, Lojek L, Khalil AM, Baker KE, Coller J
Mol Cell (2012);45(3):279-91
See PubMed abstract

Emerging Roles for Long Non-Coding RNAs in Cancer and Neurological Disorders.
Niland CN, Merry CR, Khalil AM
Front Genet (2012);3:25
See PubMed abstract

Co-Immunoprecipitation of Long Noncoding RNAs.
Moran VA, Niland CN, Khalil AM
Methods Mol Biol (2012);925:219-28
See PubMed abstract

A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response.
Huarte M, Guttman M, Feldser D, Garber M, Koziol MJ, Kenzelmann-Broz D, Khalil AM, Zuk O, Amit I, Rabani M, Attardi LD, Regev A, Lander ES, Jacks T, Rinn JL
Cell (2010);142(3):409-19
See PubMed abstract

Nucleosome occupancy landscape and dynamics at mouse recombination hotspots.
Getun IV, Wu ZK, Khalil AM, Bois PR
EMBO Rep (2010);11(7):555-60
See PubMed abstract

Epigenetic regulation of pericentromeric heterochromatin during mammalian meiosis.
Khalil AM, Driscoll DJ
Cytogenet Genome Res (2010);129(4):280-9
See PubMed abstract

Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression.
Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, Thomas K, Presser A, Bernstein BE, van Oudenaarden A, Regev A, Lander ES, Rinn JL
Proc Natl Acad Sci U S A (2009);106(28):11667-72
See PubMed abstract

Journal club. A geneticist views two theories of X-chromosome inactivation in a broad context.
Khalil AM
Nature (2009);458(7236):263
See PubMed abstract

A small molecule enhances RNA interference and promotes microRNA processing.
Shan G, Li Y, Zhang J, Li W, Szulwach KE, Duan R, Faghihi MA, Khalil AM, Lu L, Paroo Z, Chan AW, Shi Z, Liu Q, Wahlestedt C, He C, Jin P
Nat Biotechnol (2008);26(8):933-40
See PubMed abstract

Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase.
Faghihi MA, Modarresi F, Khalil AM, Wood DE, Sahagan BG, Morgan TE, Finch CE, St Laurent G, Kenny PJ, Wahlestedt C
Nat Med (2008);14(7):723-30
See PubMed abstract

A novel RNA transcript with antiapoptotic function is silenced in fragile X syndrome.
Khalil AM, Faghihi MA, Modarresi F, Brothers SP, Wahlestedt C
PLoS One (2008);3(1):e1486
See PubMed abstract

Trimethylation of histone H3 lysine 4 is an epigenetic mark at regions escaping mammalian X inactivation.
Khalil AM, Driscoll DJ
Epigenetics (2007);2(2):114-8
See PubMed abstract

Epigenetic mechanisms of gene regulation during mammalian spermatogenesis.
Khalil AM, Wahlestedt C
Epigenetics (2007);3(1):21-8
See PubMed abstract

Histone H3 lysine 4 dimethylation is enriched on the inactive sex chromosomes in male meiosis but absent on the inactive X in female somatic cells.
Khalil AM, Driscoll DJ
Cytogenet Genome Res (2006);112(1-2):11-5
See PubMed abstract

Dynamic histone modifications mark sex chromosome inactivation and reactivation during mammalian spermatogenesis.
Khalil AM, Boyar FZ, Driscoll DJ
Proc Natl Acad Sci U S A (2004);101(47):16583-7
See PubMed abstract