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Zhang, Pu

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Zhang

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Pu

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Zhang, Pu
Author's Publications: search.filters.isAuthorOfPublication.eaf47d09-366a-4d91-8400-d4aaac009aa2

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    DNMT1-interacting RNAs block gene specific DNA methylation
    (2013) Di Ruscio, Annalisa; Ebralidze, Alexander; Benoukraf, Touati; Amabile, Giovanni; Goff, Loyal; Terragni, Joylon; Figueroa, Maria Eugenia; De Figureido Pontes, Lorena Lobo; Alberich-Jorda, Meritxell; Zhang, Pu; Wu, Mengchu; D’Alò, Francesco; Melnick, Ari; Leone, Giuseppe; Ebralidze, Konstantin K.; Pradhan, Sriharsa; Rinn, John; Tenen, Daniel
    Summary DNA methylation was described almost a century ago. However, the rules governing its establishment and maintenance remain elusive. Here, we present data demonstrating that active transcription regulates levels of genomic methylation. We identified a novel RNA arising from the CEBPA gene locus critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome-scale methylation and expression profiling extended the generality of this finding to numerous gene loci. Collectively, these results delineate the nature of DNMT1-RNA interactions and suggest strategies for gene selective demethylation of therapeutic targets in disease.
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    C/EBPa controls acquisition and maintenance of adult hematopoietic stem cell quiescence
    (2013) Ye, Min; Zhang, Hong; Amabile, Giovanni; Yang, Henry; Staber, Philipp B.; Zhang, Pu; Levantini, Elena; Alberich-Jordà, Meritxell; Zhang, Junyan; Kawasaki, Akira; Tenen, Daniel
    Summary In blood, transcription factor C/EBPa is essential for myeloid differentiation and has been implicated in regulating self-renewal of fetal liver (FL) hematopoietic stem cells (HSCs). However, its function in adult HSCs has remained unknown. Here, using an inducible knockout model we found that C/EBPa deficient adult HSCs underwent a pronounced expansion with enhanced proliferation, characteristics resembling FL HSCs. Consistently, transcription profiling of C/EBPa deficient HSCs revealed a gene expression programme similar to FL HSCs. Moreover we observed that age-specific C/EBPa expression correlated with its inhibitory effect on HSC cell cycle. Mechanistically we identified N-Myc as C/EBPa downstream target, and loss of C/EBPa resulted in de-repression of N-Myc. Our data establish C/EBPa as a central determinant in the switch from fetal to adult HSCs.
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    Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia
    (American Society of Hematology, 2009) Guibal, F. C.; Alberich-Jorda, M.; Hirai, H.; Ebralidze, Alexander; Levantini, Elena; Di Ruscio, A.; Zhang, Pu; Santana-Lemos, B. A.; Neuberg, Donna; Wagers, Amy; Rego, E. M.; Tenen, Daniel
    Acute promyelocytic leukemia (APL) is characterized by a block in differentiation and accumulation of promyelocytes in the bone marrow and blood. The majority of APL patients harbor the t(15:17) translocation leading to expression of the fusion protein promyelocytic-retinoic acid receptor . Treatment with retinoic acid leads to degradation of promyelocyticretinoic acid receptor protein and disappearance of leukemic cells; however, 30% of APL patients relapse after treatment. One potential mechanism for relapse is the persistence of cancer “stem” cells in hematopoietic organs after treatment. Using a novel sorting strategy we developed to isolate murine myeloid cells at distinct stages of differentiation, we identified a population of committed myeloid cells (CD34, c-kit, FcRIII/II, Gr1int) that accumulates in the spleen and bone marrow in a murine model of APL. We observed that these cells are capable of efficiently generating leukemia in recipient mice, demonstrating that this population represents the APL cancer–initiating cell. These cells down-regulate the transcription factor CCAAT/enhancer binding protein (C/EBP) possibly through a methylationdependent mechanism, indicating that C/EBP deregulation contributes to transformation of APL cancer–initiating cells. Our findings provide further understanding of the biology of APL by demonstrating that a committed transformed progenitor can initiate and propagate the disease.