BBS Faculty Member - Alan Mullen

Alan Mullen

Department of Medicine

Massachusetts General Hospital
Thier Building, Room 306B
55 Fruit Street
Boston, MA 02114
Tel: 617-726-6342
Fax: 617-724-6518
Email: acmullen@mgh.harvard.edu
Visit my lab page here.



The vast majority of RNAs encoded by the human genome are never translated into protein, and our laboratory focuses on understanding how these noncoding RNAs regulate cell fate and cell state in human development and disease. Long noncoding (lnc) RNAs are encoding by genes with similar genomic structure to protein coding genes and have similar features to messenger (m) RNAs, but they are not translated into proteins. Instead, lncRNAs carry out their primary biological functions as RNAs, including regulation of developmental and disease processes. Many lncRNAs are cell-type-specific and are also poorly conserved across species. Thus, many of lncRNAs expressed in human cells do not have identifiable homologues in murine cells. For this reason, we focus our studies on lncRNAs in human cells or on those lncRNAs where we can identify mouse orthologs of human lncRNAs.

We focus our studies in two systems:

Human embryonic stem cell (hESC) differentiation
hESCs can be propagated indefinitely and have the potential to differentiate into any cell in the adult human body, providing tremendous potential in regenerative medicine. TGF-beta signaling is a key pathway that maintains hESC state and also drives endodermal differentiation. We use gain and loss of function approaches to determine the role of lncRNAs in the differentiation of hESCs into endoderm with a focus on those that are directly regulated by TGF-beta signaling. Through these studies, we have defined an lncRNA that regulates endoderm differentiation through interaction with a bromodomain protein and have identified additional lncRNAs that regulate endoderm differentiation.

Human hepatic stellate cells.
Hepatic stellate cells make up 5-10% of the cells in the liver and are the cell type primarily responsible for liver fibrosis. Progressive liver fibrosis is driven in large part by TGF-beta signaling and is the common endpoint in every form of chronic liver disease. Fibrosis is significant because it is the underlying cause of end stage liver disease and liver failure. We have defined the lncRNAs that are expressed in activated, fibrotic human hepatic stellate cells and are investigating the role of these lncRNAs as regulators of disease, with the goal of targeting these lncRNAs to treat fibrosis.



Last Update: 8/8/2019



Publications

For a complete listing of publications click here.

 


 

Mullen AC, Orlando DA, Newman JJ, Loven J, Kumar RM, Bilodeau S, Reddy J, Guenther MG, DeKoter RP, and Young RA. (2011). Master transcription factors determine cell-type-specific responses to TGF-beta signaling. Cell 147, 565-576.

Sigova AA, Mullen AC, Moline B, Gupta S, Orlando DA, Guenther MG, Alamada AE, Lin C, Sharp PA, Giallourakis CC, Young RA. (2013). Divergent transcription of long noncoding RNA/mRNA gene pairs in embryonic stem cells. Proceedings of the National Academy of Sciences 110, 2876-81.

Zhou C, York SR, Chen JY, Pondick J, Motola D, Chung RA, Mullen AC. (2016). Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins. Genome Medicine. 8, 31.

Daneshvar K, Pondick JV, Kim BM, Zhou C, York SR, Macklin JA, Abualteen A, Bo T, Sigova AA, Marcho C, Tremblay KD, Mager J Choi MY, Mullen AC. (2016). DIGIT Is a Conserved Long Noncoding RNA that Regulates GSC Expression to Control Definitive Endoderm Differentiation of Embryonic Stem Cells. Cell Reports. 17, 353-365.

Chen JY, Newcomb B, Zhou C, Pondick JV, Ghoshal S, York SR, Motola DL, Coant N, Yi JK, Mao C, Tanabe KK, Bronova I, Berdyshev EV, Fuchs BC, Hannun Y, Chung RT, Mullen AC. (2017). Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells. Scientific Reports. 7, 44867.

Zhou C, Molinie B, Daneshvar K, Pondick JV, Wang J, Wittenberghe NO, Xing Y, Giallourakis CC, Mullen AC. (2017). Genome-wide maps of m6A circRNAs identify widespread and cell-type-specific methylation patterns that are distinct from mRNAs. Cell Reports. 20, 2262-2276.

Daneshvar K, Ardehali MB, Klein IA, Kratkiewicz AJ, Zhou C, Mahpour A, Cook BM, Li W, Pondick JV, Moran SP, Young RA, Kingston RE, Mullen AC. (2019). lncRNA DIGIT and BRD3 protein form phase-separated condensates to regulate endoderm differentiation. bioRxiv.



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of Harvard College