title: Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers.
abstract: DNA methylation at the 5-position of cytosines (5 mC) represents an important epigenetic modification involved in tissue differentiation and is frequently altered in cancer. Recent evidence suggests that 5 mC can be converted to 5-hydroxymethylcytosine (5 hmC) in an enzymatic process involving members of the TET protein family. Such 5 hmC modifications are known to be prevalent in DNA of embryonic stem cells and in the brain, but the distribution of 5 hmC in the majority of embryonic and adult tissues has not been rigorously explored. Here, we describe an immunohistochemical detection method for 5 hmC and the application of this technique to study the distribution of 5 hmC in a large set of mouse and human tissues. We found that 5 hmC was abundant in the majority of embryonic and adult tissues. Additionally, the level of 5 hmC closely tracked with the differentiation state of cells in hierarchically organized tissues. The highest 5 hmC levels were observed in terminally differentiated cells, while less differentiated tissue stem/progenitor cell compartments had very low 5 hmC levels. Furthermore, 5 hmC levels were profoundly reduced in carcinoma of the prostate, breast and colon compared to normal tissues. Our findings suggest a distinct role for 5 hmC in tissue differentiation, and provide evidence for its large-scale loss in cancers.
authors: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
authors: Michael C
authors: MC
authors: Haffner
authors: Alcides
authors: A
authors: Chaux
authors: Alan K
authors: AK
authors: Meeker
authors: David M
authors: DM
authors: Esopi
authors: Jonathan
authors: J
authors: Gerber
authors: Laxmi G
authors: LG
authors: Pellakuru
authors: Antoun
authors: A
authors: Toubaji
authors: Pedram
authors: P
authors: Argani
authors: Christine
authors: C
authors: Iacobuzio-Donahue
authors: William G
authors: WG
authors: Nelson
authors: George J
authors: GJ
authors: Netto
authors: Angelo M
authors: AM
authors: De Marzo
authors: Srinivasan
authors: S
authors: Yegnasubramanian
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000230:Adenocarcinoma / Q000737:chemistry* / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000737:chemistry* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry* / Q000473:pathology; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000737:chemistry* / Q000473:pathology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000032:analysis; D015536:Down-Regulation; D004622:Embryo, Mammalian / Q000737:chemistry; D005260:Female; D005865:Gestational Age; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000473:pathology; D013234:Stem Cells / Q000737:chemistry*
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine