- PhD, University of North Carolina at Chapel Hill
- MSc, Sabanci University
- Postdoc, Harvard Medical School, Mass general Hosptal, Broad Institute of Harvad and MIT
Understanding and manipulating the genetics and epigenetics information to study stem cells, differentiation and cancer
The human body contains more than 200 different cell types. Although these cells are genotypically the same, i.e., they posses the same genetic information, they are functionally and phenotypically different. Our lab integrates genomic and epigenomic technologies such as RNA-Seq and ChIP-Seq as well as imaging technologies (Flow cytometry, confocal microscopy) to understand how chromatin architecture is organized and functions differently in diverse cellular states. We are particularly focused on studying chromatin biology during normal and malignant development.
Genetic information is encoded in four letters of A G C and T. All cells in the body 'read' this four letter genetic information to function. There are multiple levels of regulation during this process of 'reading' the genetic information. The primary level of regulation takes place at the DNA sequence level, in which the four letters of nucleic acids are organized in certain combinations and function as 'regulatory DNA elements' such as promoters, genes and enhancers. The secondary level of organization and regulation is controlled at the chromatin level where DNA is wrapped around special proteins called 'histone' proteins, forming nucleosomes. Nucleosomes can tightly or loosely package DNA and hence provide differential accessibility of genomic information. The tertiary level of genome regulation is dictated by the organization of nuclear architecture and long-range chromosomal interactions.
These latter two modes of genome regulation are considered epigenetic mechanisms. Epigenetics (Epi-Â in Greek means above or over) can be defined in its simplest form as the study of heritable changes in gene expression and cellular states that are not caused by changes in genetic information. There are several sources of epigenetic information. Among those, methylation of DNA cytosine residues and post-translation modifications on histone proteins are relatively better-understood components of epigenetic information. Studying these epigenetic information at the whole genome level is called Epigenomics. The study of the epigenomic maps of diverse histone modifications and DNA methylation provide unprecedented information about global chromatin landscape, organization and function.
Our lab is focused on the role chromatin organization in genome regulation during normal and malignant development such as cancer. We aim to identify epigenetic mechanisms and epigenomic features that will help us better understand the dynamic chromatin structure, function and nuclear organization during cellular differentiation programs such as stem cell self renewal and differentiation. In the lab, we apply state-of-the-art genomic and epigenomic tools and seek to develop additional technologies to answer the following specific questions.
- How are chromatin and cellular states established during normal development?
- What are the epigenetic determinants of differentiation programs of stem and progenitor cells?
- How does aberrant regulation of epigenetic information lead to cellular transformation and malignant development?
- How can we study chromatin structure in rarely available but biologically important cell populations and ultimately at single-cell-level?
- Kuscu C, Parlak M, Tufan T, Yang J, Szlachta K, Wei X, Mammadov R, Adli M. CRISPR-STOP: gene silencing through base-editing-induced nonsense mutations. Nature methods. 2017;14(7): 710-712. PMID: 28581493
- Qin P, Parlak M, Kuscu C, Bandaria J, Mir M, Szlachta K, Singh R, Darzacq X, Yildiz A, Adli M. Live cell imaging of low- and non-repetitive chromosome loci using CRISPR-Cas9. Nature communications. 2017;8 14725. PMID: 28290446 | PMCID: PMC5424063
- Ataman B, Boulting G, Harmin D, Yang M, Baker-Salisbury M, Yap E, Malik A, Mei K, Rubin A, Spiegel I, Durresi E, Sharma N, Hu L, Pletikos M, Griffith E, Partlow J, Stevens C, Adli M, Chahrour M, Sestan N, Walsh C, Berezovskii V, Livingstone M, Greenberg M. Evolution of Osteocrin as an activity-regulated factor in the primate brain. Nature. 2016;539(7628): 242-247. PMID: 27830782 | PMCID: PMC5499253
- Illendula A, Gilmour J, Grembecka J, Tirumala V, Boulton A, Kuntimaddi A, Schmidt C, Wang L, Pulikkan J, Zong H, Parlak M, Kuscu C, Pickin A, Zhou Y, Gao Y, Mishra L, Adli M, Castilla L, Rajewski R, Janes K, Guzman M, Bonifer C, Bushweller J. Small Molecule Inhibitor of CBFβ-RUNX Binding for RUNX Transcription Factor Driven Cancers. EBioMedicine. 2016;8 117-31. PMID: 27428424 | PMCID: PMC4919611
- Kuscu C, Adli M. CRISPR-Cas9-AID base editor is a powerful gain-of-function screening tool. Nature methods. 2016;13(12): 983-984. PMID: 27898061
- Adli M, Parlak M, Li Y, El-Dahr S. Epigenetic States of nephron progenitors and epithelial differentiation. Journal of cellular biochemistry. 2015;116(6): 893-902. PMID: 25560433 | PMCID: PMC4511265
- Anderson C, Clark D, Adli M, Kendall M. Correction: Ethanolamine Signaling Promotes Salmonella Niche Recognition and Adaptation during Infection. PLoS pathogens. 2015;11(12): e1005365. PMID: 26684793 | PMCID: PMC4684284
- Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller M, Amin V, Whitaker J, Schultz M, Ward L, Sarkar A, Quon G, Sandstrom R, Eaton M, Wu Y, Pfenning A, Wang X, Claussnitzer M, Liu Y, Coarfa C, Harris R, Shoresh N, Epstein C, Gjoneska E, Leung D, Xie W, Hawkins R, Lister R, Hong C, Gascard P, Mungall A, Moore R, Chuah E, Tam A, Canfield T, Hansen R, Kaul R, Sabo P, Bansal M, Carles A, Dixon J, Farh K, Feizi S, Karlic R, Kim A, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer T, Neph S, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari R, Siebenthall K, Sinnott-Armstrong N, Stevens M, Thurman R, Wu J, Zhang B, Zhou X, Beaudet A, Boyer L, De Jager P, Farnham P, Fisher S, Haussler D, Jones S, Li W, Marra M, McManus M, Sunyaev S, Thomson J, Tlsty T, Tsai L, Wang W, Waterland R, Zhang M, Chadwick L, Bernstein B, Costello J, Ecker J, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos J, Wang T, Kellis M. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539): 317-30. PMID: 25693563 | PMCID: PMC4530010
- Kuntimaddi A, Achille N, Thorpe J, Lokken A, Singh R, Hemenway C, Adli M, Zeleznik-Le N, Bushweller J. Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 Di- and tri-methylation on target genes and transformation potential. Cell reports. 2015;11(5): 808-20. PMID: 25921540 | PMCID: PMC4426023
- Qin F, Song Z, Babiceanu M, Song Y, Facemire L, Singh R, Adli M, Li H. Correction: discovery of CTCF-sensitive cis-spliced fusion RNAs between adjacent genes in human prostate cells. PLoS genetics. 2015;11(4): e1005161. PMID: 25860022 | PMCID: PMC4393099
- Singh R, Kuscu C, Quinlan A, Qi Y, Adli M. Cas9-chromatin binding information enables more accurate CRISPR off-target prediction. Nucleic acids research. 2015. PMID: 26032770 | PMCID: PMC4605288
- Kuscu C, Arslan S, Singh R, Thorpe J, Adli M. Genome-wide analysis reveals characteristics of off-target sites bound by the Cas9 endonuclease. Nature biotechnology. 2014;32(7): 677-83. PMID: 24837660
- Rissman E, Adli M. Minireview: transgenerational epigenetic inheritance: focus on endocrine disrupting compounds. Endocrinology. 2014;155(8): 2770-80. PMID: 24885575 | PMCID: PMC4098001
- Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung Y, Kuscu C, Hricik T, Ndiaye-Lobry D, Lafave L, Koche R, Shih A, Guryanova O, Kim E, Li S, Pandey S, Shin J, Telis L, Liu J, Bhatt P, Monette S, Zhao X, Mason C, Park C, Bernstein B, Aifantis I, Levine R. Deletion of Asxl1 results in myelodysplasia and severe developmental defects in vivo. The Journal of experimental medicine. 2013;210(12): 2641-59. PMID: 24218140 | PMCID: PMC3832937
- Zhu J, Adli M, Zou J, Verstappen G, Coyne M, Zhang X, Durham T, Miri M, Deshpande V, De Jager P, Bennett D, Houmard J, Muoio D, Onder T, Camahort R, Cowan C, Meissner A, Epstein C, Shoresh N, Bernstein B. Genome-wide chromatin state transitions associated with developmental and environmental cues. Cell. 2013;152(3): 642-54. PMID: 23333102 | PMCID: PMC3563935
- Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T, Liu F, Saunders L, Mullally A, Abdel-Wahab O, Leung L, Weinstein A, Marubayashi S, Goel A, Gönen M, Estrov Z, Ebert B, Chiosis G, Nimer S, Bernstein B, Verstovsek S, Levine R. Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy. Nature. 2012. PMID: 22820254 | PMCID: 22820254
- Adli M, Bernstein B. Whole-genome chromatin profiling from limited numbers of cells using nano-ChIP-seq. Nature protocols. 2011;6(10): 1656-68. PMID: 21959244 | PMCID: 21959244
- Chapman M, Lawrence M, Keats J, Cibulskis K, Sougnez C, Schinzel A, Harview C, Brunet J, Ahmann G, Adli M, Anderson K, Ardlie K, Auclair D, Baker A, Bergsagel P, Bernstein B, Drier Y, Fonseca R, Gabriel S, Hofmeister C, Jagannath S, Jakubowiak A, Krishnan A, Levy J, Liefeld T, Lonial S, Mahan S, Mfuko B, Monti S, Perkins L, Onofrio R, Pugh T, Rajkumar S, Ramos A, Siegel D, Sivachenko A, Stewart A, Trudel S, Vij R, Voet D, Winckler W, Zimmerman T, Carpten J, Trent J, Hahn W, Garraway L, Meyerson M, Lander E, Getz G, Golub T. Initial genome sequencing and analysis of multiple myeloma. Nature. 2011;471(7339): 467-72. PMID: 21430775 | PMCID: NIHMS385546
- Adli M, Merkhofer E, Cogswell P, Baldwin A. IKKalpha and IKKbeta each function to regulate NF-kappaB activation in the TNF-induced/canonical pathway. PloS one. 2010;5(2): e9428. PMID: 20195534 | PMCID: PMC2828475
- Adli M, Zhu J, Bernstein B. Genome-wide chromatin maps derived from limited numbers of hematopoietic progenitors. Nature methods. 2010;7(8): 615-8. PMID: 20622861 | PMCID: PMC2924612
- Goren A, Ozsolak F, Shoresh N, Ku M, Adli M, Hart C, Gymrek M, Zuk O, Regev A, Milos P, Bernstein B. Chromatin profiling by directly sequencing small quantities of immunoprecipitated DNA. Nature methods. 2009;7(1): 47-9. PMID: 19946276 | PMCID: PMC2862482
- Ku M, Koche R, Rheinbay E, Mendenhall E, Endoh M, Mikkelsen T, Presser A, Nusbaum C, Xie X, Chi A, Adli M, Kasif S, Ptaszek L, Cowan C, Lander E, Koseki H, Bernstein B. Genomewide analysis of PRC1 and PRC2 occupancy identifies two classes of bivalent domains. PLoS genetics. 2008;4(10): e1000242. PMID: 18974828 | PMCID: PMC2567431
- Dan H, Adli M, Baldwin A. Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alpha. Cancer research. 2007;67(13): 6263-9. PMID: 17616684 | PMCID: 17616684
- Adli M, Baldwin A. IKK-i/IKKepsilon controls constitutive, cancer cell-associated NF-kappaB activity via regulation of Ser-536 p65/RelA phosphorylation. The Journal of biological chemistry. 2006;281(37): 26976-84. PMID: 16840782 | PMCID: 16840782