PMID- 36769164
OWN - NLM
STAT- MEDLINE
DCOM- 20230217
LR  - 20240421
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 3
DP  - 2023 Feb 2
TI  - Epigenetic Regulation of Corneal Epithelial Differentiation by TET2.
LID - 10.3390/ijms24032841 [doi]
LID - 2841
AB  - Epigenetic DNA modification by 5-hydroxymethylcytosine (5hmC), generated by the 
      Ten-eleven translocation (TET) dioxygenases, regulates diverse biological 
      functions in many organ tissues, including the mammalian eye. For example, 5hmC 
      has been shown to be involved in epigenetic regulation of retinal gene 
      expression. However, a functional role of 5hmC in corneal differentiation has not 
      been investigated to date. Here, we examined 5hmC and TET function in the human 
      cornea. We found 5hmC highly expressed in MUC16-positive terminally 
      differentiated cells that also co-expressed the 5hmC-generating enzyme TET2. TET2 
      knockdown (KD) in cultured corneal epithelial cells led to significant reductions 
      of 5hmC peak distributions and resulted in transcriptional repression of 
      molecular pathways involved in corneal differentiation, as evidenced by 
      downregulation of MUC4, MUC16, and Keratin 12. Additionally, integrated TET2 KD 
      RNA-seq and genome-wide Reduced Representation Hydroxymethylation Profiling 
      revealed novel epigenetically regulated genes expressed by terminally 
      differentiated cells, including KRT78, MYEOV, and MAL. In aggregate, our findings 
      reveal a novel function of TET2 in the epigenetic regulation of corneal 
      epithelial gene expression and identify novel TET2-controlled genes expressed in 
      differentiated corneal epithelial cells. These results point to potential roles 
      for TET2 induction strategies to enhance treatment of corneal diseases associated 
      with abnormal epithelial maturation.
FAU - Sasamoto, Yuzuru
AU  - Sasamoto Y
AD  - Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
AD  - Transplant Research Program, Boston Children's Hospital, Boston, MA 02115, USA.
FAU - Wu, Siyuan
AU  - Wu S
AD  - Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
AD  - Transplant Research Program, Boston Children's Hospital, Boston, MA 02115, USA.
FAU - Lee, Catherine A A
AU  - Lee CAA
AUID- ORCID: 0000-0001-8525-9342
AD  - Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
FAU - Jiang, Jason Y
AU  - Jiang JY
AD  - Transplant Research Program, Boston Children's Hospital, Boston, MA 02115, USA.
FAU - Ksander, Bruce R
AU  - Ksander BR
AD  - Massachusetts Eye & Ear Infirmary, Schepens Eye Research Institute, Boston, MA 
      02114, USA.
FAU - Frank, Markus H
AU  - Frank MH
AUID- ORCID: 0000-0002-1312-0488
AD  - Transplant Research Program, Boston Children's Hospital, Boston, MA 02115, USA.
AD  - Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
AD  - Harvard Skin Disease Research Center, Department of Dermatology, Brigham and 
      Women's Hospital, Boston, MA 02115, USA.
AD  - School of Medical and Health Sciences, Edith Cowan University, Perth 6027, WA, 
      Australia.
FAU - Frank, Natasha Y
AU  - Frank NY
AD  - Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
AD  - Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
AD  - Department of Medicine, VA Boston Healthcare System, Boston, MA 02132, USA.
LA  - eng
GR  - R24 EY028767/EY/NEI NIH HHS/United States
GR  - R00 EY031741/EY/NEI NIH HHS/United States
GR  - K99 EY031741/EY/NEI NIH HHS/United States
GR  - P01 AG071463/AG/NIA NIH HHS/United States
GR  - P30 EY003790/EY/NEI NIH HHS/United States
GR  - T32 EB016652/EB/NIBIB NIH HHS/United States
GR  - R01 HL161087/HL/NHLBI NIH HHS/United States
GR  - R01 EY025794/EY/NEI NIH HHS/United States
GR  - I01 RX000989/RX/RRD VA/United States
PT  - Journal Article
DEP - 20230202
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 6R795CQT4H (5-Methylcytosine)
RN  - EC 1.13.11.- (Dioxygenases)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 1.13.11.- (TET2 protein, human)
SB  - IM
MH  - Humans
MH  - 5-Methylcytosine/metabolism
MH  - Cell Differentiation/genetics
MH  - Cornea/metabolism
MH  - *Dioxygenases/genetics/metabolism
MH  - DNA Methylation
MH  - DNA-Binding Proteins/metabolism
MH  - *Epigenesis, Genetic
MH  - Mammals/metabolism
MH  - Proto-Oncogene Proteins/metabolism
PMC - PMC9917645
OTO - NOTNLM
OT  - 5-hydroxymethylcytosine (5hmC)
OT  - KRT78
OT  - MAL
OT  - MYEOV
OT  - TET2
OT  - corneal epithelium
OT  - differentiation
OT  - genome-wide 5hmC analysis
COIS- M.H.F., B.R.K. and N.Y.F. are inventors or co-inventors of US and international 
      patents assigned to Brigham and Women's Hospital, Boston Children's Hospital, the 
      Massachusetts Eye and Ear Infirmary, and/or the VA Boston Healthcare System, 
      Boston, MA, licensed to Ticeba GmbH (Heidelberg, Germany) and Rheacell GmbH & Co. 
      KG (Heidelberg, Germany). M.H.F. serves as a scientific advisor to and holds 
      stock in Ticeba GmbH and Rheacell GmbH & Co. KG.
EDAT- 2023/02/12 06:00
MHDA- 2023/02/15 06:00
PMCR- 2023/02/02
CRDT- 2023/02/11 01:24
PHST- 2022/11/05 00:00 [received]
PHST- 2023/01/19 00:00 [revised]
PHST- 2023/01/21 00:00 [accepted]
PHST- 2023/02/11 01:24 [entrez]
PHST- 2023/02/12 06:00 [pubmed]
PHST- 2023/02/15 06:00 [medline]
PHST- 2023/02/02 00:00 [pmc-release]
AID - ijms24032841 [pii]
AID - ijms-24-02841 [pii]
AID - 10.3390/ijms24032841 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Feb 2;24(3):2841. doi: 10.3390/ijms24032841.