Wilms tumor chromatin profiles highlight stem cell properties and a renal developmental network.
Wilms tumor is the most common pediatric kidney cancer. To identify transcriptional and epigenetic mechanisms that drive this disease, we compared genome-wide chromatin profiles of Wilms tumors, embryonic stem cells (ESCs), and normal kidney. Wilms tumors prominently exhibit large active chromatin domains previously observed in ESCs. In the cancer, these domains frequently correspond to genes that are critical for kidney development and expressed in the renal stem cell compartment. Wilms cells also express "embryonic" chromatin regulators and maintain stem cell-like p16 silencing. Finally, Wilms and ESCs both exhibit "bivalent" chromatin modifications at silent promoters that may be poised for activation. In Wilms tumor, bivalent promoters correlate to genes expressed in specific kidney compartments and point to a kidney-specific differentiation program arrested at an early-progenitor stage. We suggest that Wilms cells share a transcriptional and epigenetic landscape with a normal renal stem cell, which is inherently susceptible to transformation and may represent a cell of origin for this disease.
Aiden
Aviva Presser
AP
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Rivera
Miguel N
MN
Rheinbay
Esther
E
Ku
Manching
M
Coffman
Erik J
EJ
Truong
Thanh T
TT
Vargas
Sara O
SO
Lander
Eric S
ES
Haber
Daniel A
DA
Bernstein
Bradley E
BE
D048868:Adaptor Proteins, Signal Transducing; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics; D009396:Wilms Tumor / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology
C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C000614131:CDKN2A protein, human; D002843:Chromatin; D019941:Cyclin-Dependent Kinase Inhibitor p16; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins