Transcriptional, epigenetic and retroviral signatures identify regulatory regions involved in hematopoietic lineage commitment.
Genome-wide approaches allow investigating the molecular circuitry wiring the genetic and epigenetic programs of human somatic stem cells. Hematopoietic stem/progenitor cells (HSPC) give rise to the different blood cell types; however, the molecular basis of human hematopoietic lineage commitment is poorly characterized. Here, we define the transcriptional and epigenetic profile of human HSPC and early myeloid and erythroid progenitors by a combination of Cap Analysis of Gene Expression (CAGE), ChIP-seq and Moloney leukemia virus (MLV) integration site mapping. Most promoters and transcripts were shared by HSPC and committed progenitors, while enhancers and super-enhancers consistently changed upon differentiation, indicating that lineage commitment is essentially regulated by enhancer elements. A significant fraction of CAGE promoters differentially expressed upon commitment were novel, harbored a chromatin enhancer signature, and may identify promoters and transcribed enhancers driving cell commitment. MLV-targeted genomic regions co-mapped with cell-specific active enhancers and super-enhancers. Expression analyses, together with an enhancer functional assay, indicate that MLV integration can be used to identify bona fide developmentally regulated enhancers. Overall, this study provides an overview of transcriptional and epigenetic changes associated to HSPC lineage commitment, and a novel signature for regulatory elements involved in cell identity.
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.|Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy.|INSERM UMR 1163, Laboratory of chromatin and gene regulation during development, Paris, France.
Oriana
O
Romano
Institute of Biomedical Technologies, CNR, Milan, Italy.
Clelia
C
Peano
Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy.
Guidantonio Malagoli
GM
Tagliazucchi
Institute of Biomedical Technologies, CNR, Milan, Italy.
Luca
L
Petiti
Genethon, Evry, France.
Valentina
V
Poletti
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Fabienne
F
Cocchiarella
Institute of Biomedical Technologies, CNR, Milan, Italy.|Telethon Foundation, Milan, Italy.
Ermanno
E
Rizzi
Institute of Biomedical Technologies, CNR, Milan, Italy.
Marco
M
Severgnini
Dana Farber Cancer Institute, Harvard Medical School, Boston, US.
Alessia
A
Cavazza
San Raffaele-Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, Milan, Italy.
Claudia
C
Rossi
Az. Osp. Policlinico Universitario di Bologna, Policlinico S. Orsola-Malpighi, Unità Operativa di Immunoematologia e Trasfusionale, Bologna, Italy.
Pasqualepaolo
P
Pagliaro
Vita Salute San Raffaele University, Milan, Italy.
Alessandro
A
Ambrosi
San Raffaele-Telethon Institute for Gene Therapy (TIGET), San Raffaele Scientific Institute, Milan, Italy.|Vita Salute San Raffaele University, Milan, Italy.
Giuliana
G
Ferrari
Center for Genomic Research, University of Modena and Reggio Emilia, Modena, Italy.
Silvio
S
Bicciato
Institute of Biomedical Technologies, CNR, Milan, Italy.
Gianluca
G
De Bellis
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.|Genethon, Evry, France.
Fulvio
F
Mavilio
Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.|INSERM UMR 1163, Laboratory of chromatin and gene regulation during development, Paris, France.|Paris Descartes, Sorbonne Paris Cité University, Imagine Institute, Paris, France.
Annarita
A
Miccio
D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics*; D016384:Consensus Sequence; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D015967:Gene Expression Regulation, Viral; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D039902:Multipotent Stem Cells / Q000166:cytology; D009928:Organ Specificity; D056510:Position-Specific Scoring Matrices; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D012190:Retroviridae / Q000235:genetics*; D061785:Transcription Initiation, Genetic; D059467:Transcriptome
D006657:Histones