Robert Blelloch, MD, PhD

Professor
Department of Urology
BlellochR@stemcell.ucsf.edu

Our laboratory is interested in determining the molecular mechanisms that regulate stem cell differentiation and de-differentiation and how these mechanisms become deregulated in cancer.  Since starting the lab in 2006, we have been largely focusing on the role of post-transcriptional regulators including microRNAs (miRNAs) and RNA binding proteins (RBPs).

Embryonic Stem Cells
We have shown that a specific family of miRNAs, which we call the ESCC family, is a powerful inducer and stabilizer of the mammalian embryonic stem cell (ESC) fate.  We found that this family suppresses hundreds of downstream mRNA targets. By following a subset of these targets, we now know that the ESCC miRNAs function in part by directing the unique cell cycle structure, the epithelial state, and the epigenetic state of ESCs. We are currently dissecting the role of all the ESCC miRNA downstream targets in pluripotency. In parallel, we have uncovered other miRNAs that have the opposite function to the ESCC miRNAs in that they promote differentiation.  Indeed the differentiating miRNAs are antagonized by the ESCC miRNAs.  We are dissecting the mechanisms of these miRNAs in ESC differentiation.  Furthermore, we are studying the roles of the ESCC miRNAs in vivo. The ESCC miRNAs are expressed from two genetic loci. We are using genetic tools to understand their role in mammalian development.

Somatic Stem and Germ Cells
The lab is also studying the role of small RNAs in other stem cell types and in vivo developmental stages. In particular, we are studying miRNA roles in trophoblast stem cells, glial progenitor cells, and oocytes. We recently made the surprising finding that miRNA function is globally suppressed in mammalian oocytes. We are following up this finding by trying to understand how and why all miRNA function is temporarily inactivated during this critical developmental time window. Simultaneously, we discovered that another class of small RNAs, endogenous siRNA (endo-siRNAs) are essential for oocyte meiosis. We are currently dissecting the specific endo-siRNAs and targets responsible for meiotic progression.

Prostate Cancer
Finally, we are studying the roles of miRNAs in cancer with a particular focus on prostate cancer. We have discovered that miRNAs are essential for the progression of prostate cancer from a hyperplastic to dysplastic lesion. Similar to our ESC work, we are using genomic approaches to uncover the miRNA-mRNA networks in order to dissect the molecular pathways required for progression. Furthermore, we have been analyzing miRNA signatures in the serum of prostate cancer patients, identifying miRNAs that prospectively identify patients at risk for progression and determine how they will respond to specific therapies.

Research Summary: 
Molecular basis of stem cell self-renewal, differentiation and contribution to cancer

Websites

Publications: 

The eutheria-specific miR-290/miR-371 cluster modulates placental growth and maternal-fetal transport.

Development (Cambridge, England)

Paikari A, Belair C, Saw D, Blelloch R

NF45 and NF90/NF110 coordinately regulate ESC pluripotency and differentiation.

RNA (New York, N.Y.)

Ye J, Jin H, Pankov A, Song JS, Blelloch R

Patterning of sharp cellular interfaces with a reconfigurable elastic substrate.

Integrative biology : quantitative biosciences from nano to macro

Curtis A, Li DJ, DeVeale B, Onishi K, Kim MY, Blelloch R, Laird DJ, Hui EE

The impact of microRNAs on transcriptional heterogeneity and gene co-expression across single embryonic stem cells.

Nature communications

Gambardella G, Carissimo A, Chen A, Cutillo L, Nowakowski TJ, di Bernardo D, Blelloch R

Vitamin C and l-Proline Antagonistic Effects Capture Alternative States in the Pluripotency Continuum.

Stem cell reports

D'Aniello C, Habibi E, Cermola F, Paris D, Russo F, Fiorenzano A, Di Napoli G, Melck DJ, Cobellis G, Angelini C, Fico A, Blelloch R, Motta A, Stunnenberg HG, De Cesare D, Patriarca EJ, Minchiotti G

miRNAs Are Essential for the Regulation of the PI3K/AKT/FOXO Pathway and Receptor Editing during B Cell Maturation.

Cell reports

Coffre M, Benhamou D, Rieß D, Blumenberg L, Snetkova V, Hines MJ, Chakraborty T, Bajwa S, Jensen K, Chong MM, Getu L, Silverman GJ, Blelloch R, Littman DR, Calado D, Melamed D, Skok JA, Rajewsky K, Koralov SB

A miR-372/let-7 Axis Regulates Human Germ Versus Somatic Cell Fates.

Stem cells (Dayton, Ohio)

Tran ND, Kissner M, Subramanyam D, Parchem RJ, Laird DJ, Blelloch RH

FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity.

Cell stem cell

Krishnakumar R, Chen AF, Pantovich MG, Danial M, Parchem RJ, Labosky PA, Blelloch R

Fas-Activated Mitochondrial Apoptosis Culls Stalled Embryonic Stem Cells to Promote Differentiation.

Current biology : CB

Wang ES, Reyes NA, Melton C, Huskey NE, Momcilovic O, Goga A, Blelloch R, Oakes SA

Biogenesis, delivery, and function of extracellular RNA.

Journal of extracellular vesicles

Patton JG, Franklin JL, Weaver AM, Vickers K, Zhang B, Coffey RJ, Ansel KM, Blelloch R, Goga A, Huang B, L'Etoille N, Raffai RL, Lai CP, Krichevsky AM, Mateescu B, Greiner VJ, Hunter C, Voinnet O, McManus MT

miR-302 Is Required for Timing of Neural Differentiation, Neural Tube Closure, and Embryonic Viability.

Cell reports

Parchem RJ, Moore N, Fish JL, Parchem JG, Braga TT, Shenoy A, Oldham MC, Rubenstein JL, Schneider RA, Blelloch R

DGCR8 is essential for tumor progression following PTEN loss in the prostate.

EMBO reports

Belair CD, Paikari A, Moltzahn F, Shenoy A, Yau C, Dall'Era M, Simko J, Benz C, Blelloch R

Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro.

The EMBO journal

Russ HA, Parent AV, Ringler JJ, Hennings TG, Nair GG, Shveygert M, Guo T, Puri S, Haataja L, Cirulli V, Blelloch R, Szot GL, Arvan P, Hebrok M

CDK1 inhibition targets the p53-NOXA-MCL1 axis, selectively kills embryonic stem cells, and prevents teratoma formation.

Stem cell reports

Huskey NE, Guo T, Evason KJ, Momcilovic O, Pardo D, Creasman KJ, Judson RL, Blelloch R, Oakes SA, Hebrok M, Goga A

Let-7 and miR-125 cooperate to prime progenitors for astrogliogenesis.

The EMBO journal

Shenoy A, Danial M, Blelloch RH

Early postnatal ablation of the microRNA-processing enzyme, Drosha, causes chondrocyte death and impairs the structural integrity of the articular cartilage.

Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society

Kobayashi T, Papaioannou G, Mirzamohammadi F, Kozhemyakina E, Zhang M, Blelloch R, Chong MW

Suppression of epithelial-mesenchymal transition and apoptotic pathways by miR-294/302 family synergistically blocks let-7-induced silencing of self-renewal in embryonic stem cells.

Cell death and differentiation

Guo WT, Wang XW, Yan YL, Li YP, Yin X, Zhang Q, Melton C, Shenoy A, Reyes NA, Oakes SA, Blelloch R, Wang Y

Regulation of microRNA function in somatic stem cell proliferation and differentiation.

Nature reviews. Molecular cell biology

Shenoy A, Blelloch RH

miR-19, miR-345, miR-519c-5p serum levels predict adverse pathology in prostate cancer patients eligible for active surveillance.

PloS one

Wang SY, Shiboski S, Belair CD, Cooperberg MR, Simko JP, Stoppler H, Cowan J, Carroll PR, Blelloch R

Two miRNA clusters reveal alternative paths in late-stage reprogramming.

Cell stem cell

Parchem RJ, Ye J, Judson RL, LaRussa MF, Krishnakumar R, Blelloch A, Oldham MC, Blelloch R

MicroRNA-based discovery of barriers to dedifferentiation of fibroblasts to pluripotent stem cells.

Nature structural & molecular biology

Judson RL, Greve TS, Parchem RJ, Blelloch R

Epigenetics of cellular reprogramming.

Current opinion in genetics & development

Krishnakumar R, Blelloch RH

Regulation of epithelial-mesenchymal and mesenchymal-epithelial transitions by microRNAs.

Current opinion in cell biology

Lamouille S, Subramanyam D, Blelloch R, Derynck R

Small RNAs in germline development.

Current topics in developmental biology

Cook MS, Blelloch R

An integrated nano-scale approach to profile miRNAs in limited clinical samples.

American journal of clinical and experimental immunology

Seumois G, Vijayanand P, Eisley CJ, Omran N, Kalinke L, North M, Ganesan AP, Simpson LJ, Hunkapiller N, Moltzahn F, Woodruff PG, Fahy JV, Erle DJ, Djukanovic R, Blelloch R, Ansel KM

Sox1 marks an activated neural stem/progenitor cell in the hippocampus.

Development (Cambridge, England)

Venere M, Han YG, Bell R, Song JS, Alvarez-Buylla A, Blelloch R

Loss of microRNAs in pyramidal neurons leads to specific changes in inhibitory synaptic transmission in the prefrontal cortex.

Molecular and cellular neurosciences

Hsu R, Schofield CM, Dela Cruz CG, Jones-Davis DM, Blelloch R, Ullian EM

Generation of induced pluripotent stem cells from the prairie vole.

PloS one

Manoli DS, Subramanyam D, Carey C, Sudin E, Van Westerhuyzen JA, Bales KL, Blelloch R, Shah NM

Efficiency and specificity in microRNA biogenesis.

Nature structural & molecular biology

Barad O, Mann M, Chapnik E, Shenoy A, Blelloch R, Barkai N, Hornstein E

microRNA induced transdifferentiation.

F1000 biology reports

Shenoy A, Blelloch R

Dgcr8 controls neural crest cells survival in cardiovascular development.

Developmental biology

Chapnik E, Sasson V, Blelloch R, Hornstein E

MicroRNA-29 regulates T-box transcription factors and interferon-? production in helper T cells.

Immunity

Steiner DF, Thomas MF, Hu JK, Yang Z, Babiarz JE, Allen CD, Matloubian M, Blelloch R, Ansel KM

High throughput microRNA profiling: optimized multiplex qRT-PCR at nanoliter scale on the fluidigm dynamic arrayTM IFCs.

Journal of visualized experiments : JoVE

Moltzahn F, Hunkapiller N, Mir AA, Imbar T, Blelloch R

From microRNAs to targets: pathway discovery in cell fate transitions.

Current opinion in genetics & development

Subramanyam D, Blelloch R

Small RNAs in early mammalian development: from gametes to gastrulation.

Development (Cambridge, England)

Suh N, Blelloch R

Multiple targets of miR-302 and miR-372 promote reprogramming of human fibroblasts to induced pluripotent stem cells.

Nature biotechnology

Subramanyam D, Lamouille S, Judson RL, Liu JY, Bucay N, Derynck R, Blelloch R

Genome-wide analysis of translation reveals a critical role for deleted in azoospermia-like (Dazl) at the oocyte-to-zygote transition.

Genes & development

Chen J, Melton C, Suh N, Oh JS, Horner K, Xie F, Sette C, Blelloch R, Conti M

Cell cycle regulation by microRNAs in stem cells.

Results and problems in cell differentiation

Wang Y, Blelloch R

Microfluidic-based multiplex qRT-PCR identifies diagnostic and prognostic microRNA signatures in the sera of prostate cancer patients.

Cancer research

Moltzahn F, Olshen AB, Baehner L, Peek A, Fong L, Stöppler H, Simko J, Hilton JF, Carroll P, Blelloch R

On the streets of San Francisco: highlights from the ISSCR Annual Meeting 2010.

Cell stem cell

Elefanty AG, Blelloch R, Passegué E, Wernig M, Mummery CL

miR-380-5p represses p53 to control cellular survival and is associated with poor outcome in MYCN-amplified neuroblastoma.

Nature medicine

Swarbrick A, Woods SL, Shaw A, Balakrishnan A, Phua Y, Nguyen A, Chanthery Y, Lim L, Ashton LJ, Judson RL, Huskey N, Blelloch R, Haber M, Norris MD, Lengyel P, Hackett CS, Preiss T, Chetcuti A, Sullivan CS, Marcusson EG, Weiss W, L'Etoile N, Goga A

PML-RAR{alpha} and Dnmt3a1 cooperate in vivo to promote acute promyelocytic leukemia.

Cancer research

Subramanyam D, Belair CD, Barry-Holson KQ, Lin H, Kogan SC, Passegué E, Blelloch R

Distinct requirements of microRNAs in NK cell activation, survival, and function.

Journal of immunology (Baltimore, Md. : 1950)

Bezman NA, Cedars E, Steiner DF, Blelloch R, Hesslein DG, Lanier LL

MicroRNAs control hepatocyte proliferation during liver regeneration.

Hepatology (Baltimore, Md.)

Song G, Sharma AD, Roll GR, Ng R, Lee AY, Blelloch RH, Frandsen NM, Willenbring H

Mammalian microRNAs: experimental evaluation of novel and previously annotated genes.

Genes & development

Chiang HR, Schoenfeld LW, Ruby JG, Auyeung VC, Spies N, Baek D, Johnston WK, Russ C, Luo S, Babiarz JE, Blelloch R, Schroth GP, Nusbaum C, Bartel DP

MicroRNA function is globally suppressed in mouse oocytes and early embryos.

Current biology : CB

Suh N, Baehner L, Moltzahn F, Melton C, Shenoy A, Chen J, Blelloch R

MicroRNA Regulation of Embryonic Stem Cell Self-Renewal and Differentiation.

Advances in experimental medicine and biology

Melton C, Blelloch R

Watching reprogramming in real time.

Nature biotechnology

Subramanyam D, Blelloch R

Loss of cardiac microRNA-mediated regulation leads to dilated cardiomyopathy and heart failure.

Circulation research

Rao PK, Toyama Y, Chiang HR, Gupta S, Bauer M, Medvid R, Reinhardt F, Liao R, Krieger M, Jaenisch R, Lodish HF, Blelloch R

Embryonic stem cell-specific microRNAs promote induced pluripotency.

Nature biotechnology

Judson RL, Babiarz JE, Venere M, Blelloch R

Posttranscriptional crossregulation between Drosha and DGCR8.

Cell

Han J, Pedersen JS, Kwon SC, Belair CD, Kim YK, Yeom KH, Yang WY, Haussler D, Blelloch R, Kim VN

Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation.

Nature genetics

Wang Y, Baskerville S, Shenoy A, Babiarz JE, Baehner L, Blelloch R

CompMoby: comparative MobyDick for detection of cis-regulatory motifs.

BMC bioinformatics

Chaivorapol C, Melton C, Wei G, Yeh RF, Ramalho-Santos M, Blelloch R, Li H

Generation of induced pluripotent stem cells in the absence of drug selection.

Cell stem cell

Blelloch R, Venere M, Yen J, Ramalho-Santos M

DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal.

Nature genetics

Wang Y, Medvid R, Melton C, Jaenisch R, Blelloch R

Nuclear cloning of embryonal carcinoma cells.

Proceedings of the National Academy of Sciences of the United States of America

Blelloch RH, Hochedlinger K, Yamada Y, Brennan C, Kim M, Mintz B, Chin L, Jaenisch R

TRA-1/GLI controls development of somatic gonadal precursors in C. elegans.

Development (Cambridge, England)

Mathies LD, Schvarzstein M, Morphy KM, Blelloch R, Spence AM, Kimble J

Reprogramming of a melanoma genome by nuclear transplantation.

Genes & development

Hochedlinger K, Blelloch R, Brennan C, Yamada Y, Kim M, Chin L, Jaenisch R

Nuclear transplantation, embryonic stem cells and the potential for cell therapy.

The hematology journal : the official journal of the European Haematology Association / EHA

Hochedlinger K, Rideout WM, Kyba M, Daley GQ, Blelloch R, Jaenisch R

Nuclear cloning, epigenetic reprogramming, and cellular differentiation.

Cold Spring Harbor symposia on quantitative biology

Jaenisch R, Hochedlinger K, Blelloch R, Yamada Y, Baldwin K, Eggan K

The gon-1 gene is required for gonadal morphogenesis in Caenorhabditis elegans.

Developmental biology

Blelloch R, Anna-Arriola SS, Gao D, Li Y, Hodgkin J, Kimble J

Control of cell migration during Caenorhabditis elegans development.

Current opinion in cell biology

Blelloch R, Newman C, Kimble J

Roles of the RAM and ANK domains in signaling by the C. elegans GLP-1 receptor.

The EMBO journal

Roehl H, Bosenberg M, Blelloch R, Kimble J

A molecular genetic model of human bladder cancer pathogenesis.

Seminars in oncology

Reznikoff CA, Belair CD, Yeager TR, Savelieva E, Blelloch RH, Puthenveettil JA, Cuthill S