Germ cells transmit totipotency and generate genetic diversity from one generation to the next. When sperm and egg fuse, a new life begins to develop by their genetic blueprints while incorporating epigenetic instructions. Kehkooi and his research team are fascinated by these processes and focus on understanding the molecular mechanisms underlying these processes, especially RNA binding proteins involved in regulating germ cell development, initiation of meiosis, and molecular and genetic factors causing infertility. Studies of human germ cell development, especially early germ cells, had been hindered by sample procurement and variation among different individuals. Human embryonic stem cells provide them unprecedented opportunity to develop in vitro differentiation systems to study these mechanisms. They have successfully built many novel in vitro differentiation and induction systems for human germ cells and their neighboring somatic cells, including spermatids, oocytes, and Sertoli cells. These in vitro systems also allow them to study the effect of microgravity on development of human germ cells in spacecraft. Moreover, the research team have induced human stem cells to Sertoli cells which create an immune-privileged microenvironment and applied the technology to eradicate immune rejection during tissue transplantation.

The research conducted by Dr. Kee’s team centers on understanding human stem cell and germ cell development, the initiation of meiosis, and developing cell therapy to treat human diseases. Current projects include the development of in vitro models of human germ cell development and the study of infertility-causing mutations. Dr. Kee’s work has been published in several academic journals, including Nature, Developmental Cell, Nature Communications, Human Reproduction Update. His team has developed in vitro differentiation methods for transforming human pluripotent stem cells into various cell types. These methods have been applied in a range of research contexts, including China’s space projects to study the impact of microgravity on human germ cell development.

Tsinghua University ‘Outstanding Teaching Award’ (2014)

Janssen Investigator Award (2014)

Ten Outstanding Young Malaysian (Scientific and Technological development) (2011)

Bayer Investigator Award (2010, 2011, 2017)

Phi Beta Kappa Honor Society, USA (1996)

Golden Key National Honor Society, USA (1995)

Howard Hughes Medical Institute Undergraduate Research Award (1993）

1) Wen F, Ding Y, Wang M, Du J, Zhang S, Kee K*. FOXL2 and NR5A1 induce human fibroblasts into steroidogenic ovarian granulosa-like cells. Cell Prolif. 2024 Jan 8:e13589.

Link to publication: doi: 10.1111/cpr.13589

Link to Pubmed: PMID: 38192172

2) Ding Y, He Z, Sha Y, Kee K*, Li L*. Eif4enif1 haploinsufficiency disrupts oocyte

mitochondrial dynamics and leads to subfertility. Development. 2023 Dec 1;150(23):dev202151.

Link to publication: doi: 10.1242/dev.202151

Link to Pubmed: PMID: 38088064

3) He J, Yan A, Chen B, Huang J, Kee K*. 3D genome remodeling and homologous pairing during meiotic prophase of mouse oogenesis and spermatogenesis. Dev Cell. 2023 Nov 13: S1534-5807(23)00553-1.

Link to publication: doi: 10.1016/j.devcel.2023.10.009

Link to Pubmed: PMID: 37963468

4) Huang J, Chen P, Jia L, Li T, Yang X, Liang Q, Zeng Y, Liu J, Wu T, Hu W, Kee K*, Zeng H*, Liang X*, Zhou C*. Multi-Omics Analysis Reveals Translational Landscapes and Regulations in Mouse and Human Oocyte Aging. Adv Sci (Weinh). 2023 Sep;10(26):e2301538.

Link to publication: doi: 10.1002/advs.202301538

Link to Pubmed: PMID: 37401155

5) Wang N, He J, Feng X, Liao S, Zhao Y, Tang F, Kee K*. Single-cell profiling of lncRNAs in human germ cells and molecular analysis reveals transcriptional regulation of LNC1845 on LHX8. Elife. 2023 Jan 5;12:e78421.

Link to publication: doi: 10.7554/eLife.78421

Link to Pubmed: PMID: 36602025

6) Yan A, Xiong J, Zhu J, Li X, Xu S, Feng X, Ke X, Wang Z, Chen Y, Wang HW, Zhang MQ*, Kee K*. DAZL regulates proliferation of human primordial germ cells by direct binding to precursor miRNAs and enhances DICER processing activity. Nucleic Acids Res. 2022 Oct 24:gkac856.

Link to publication: doi: 10.1093/nar/gkac856

Link to Pubmed: PMID: 36273819

7) Hu W, Zeng H, Shi Y, Zhou C, Huang J, Jia L, Xu S, Feng X, Zeng Y, Xiong T, Huang W, Sun P, Chang Y, Li T, Fang C, Wu K, Cai L, Ni W, Li Y, Yang Z, Zhang QC, Chian R, Chen Z, Liang X*, Kee K*. Single-cell transcriptome and translatome dual-omics reveals potential mechanisms of human oocyte maturation. Nat Commun. 2022 Aug 30;13(1):5114.

Link to publication: doi: 10.1038/s41467-022-32791-2

Link to Pubmed: PMID: 36042231

8) Wang Y, Xie H, Chang X, Hu W, Li M, Li Y, Liu H, Cheng H, Wang S, Zhou L, Shen D, Dou S, Ma R, Mao Y, Zhu H, Zhang X, Zheng Y, Ye X, Wen L, Kee K*, Cui H*, Tang F*. Single-cell dissection of the multiomic landscape of high-grade serous ovarian cancer. Cancer Res. 2022 Aug 15:CAN-21-3819. Epub ahead of print.

Link to publication: doi: 10.1158/0008-5472.CAN-21-3819

Link to Pubmed: PMID: 35969151

9) Chen B, Zhu G, Yan A, He J, Liu Y, Li L, Yang X, Dong C, Kee K*. IGSF11 is required for pericentric heterochromatin dissociation during meiotic diplotene. PLoS Genet. 2021 Sep 7;17(9):e1009778.

Link to publication: doi: 10.1371/journal.pgen.1009778

Link to Pubmed: PMID: 34491997

10) Li L, Yang R, Yin C, Kee K*. Studying human reproductive biology through single-cell analysis and in vitro differentiation of stem cells into germ cell-like cells. Hum Reprod Update. 2020 Sep 1;26(5):670-688.

Link to publication: doi:10.1093/humupd/dmaa021

Link to Pubmed: PMID: 32464645

11) Ye M, Yang ZY, Zhang Y, Xing YX, Xie QG, Zhou JH, Wang L, Xie W, Kee K*, Chian RC*. Single-cell multiomic analysis of in vivo and in vitro matured human oocytes. Hum Reprod. 2020 Apr 28;35(4):886-900.

Link to publication: doi: 10.1093/humrep/deaa044

Link to Pubmed: PMID: 32325493

12) Liang J, Wang N, He J, Du J, Guo Y, Li L, Wu W, Yao C, Li Z, Kee K*. Induction of Sertoli-like cells from human fibroblasts by NR5A1 and GATA4. Elife. 2019 Nov 11;8. pii: e48767.

Link to publication: doi: 10.7554/eLife.48767

Link to Pubmed: PMID: 31710289

13) Wang B, Li L, Zhu Y, Zhang W, Wang X, Chen B, Li T, Pan H, Wang J, Kee K*, Cao Y*. Sequence variants of KHDRBS1 as high penetrance susceptibility risks for primary ovarian insufficiency by mis-regulating mRNA alternative splicing. Hum Reprod.2017 Oct 1;32(10):2138-2146.

Link to publication: doi: 10.1093/humrep/dex263

Link to Pubmed: PMID: 28938739

14) Jung D, Xiong J, Ye M, Qin X, Li L, Cheng S, Luo M, Peng J, Dong J, Tang F, Shen W, Matzuk MM, Kee K*. In vitro differentiation of human embryonic stem cells into ovarian follicle-like cells. Nat Commun.2017 Jun 12;8:15680.

Link to publication: doi:10.1038/ncomms15680

Link to Pubmed: PMID: 28604658

15) Li L, Wang B, Zhang W, Chen B, Luo M, Wang J, Wang X, Cao Y*, Kee K*. (2017). A homozygous NOBOX truncating variant causes defective transcriptional activation and leads to primary ovarian insufficiency. Hum Reprod 32(1): 248-255.

Link to publication: doi: 10.1093/humrep/dew271

Link to Pubmed: PMID: 27836978

16) He Z, Kee K*. (2017). Generating a Genome Editing Nuclease for Targeted Mutagenesis in Human Cells. Methods Mol Biol 1498: 153-162.

Link to publication: doi:10.1007/978-1-4939-6472-7_10

Link to Pubmed: PMID: 27709574

17) Zhang B, Zheng H, Huang B, Li W, Xiang Y, Peng X, Ming J, Wu X, Zhang Y, Xu Q, Liu W, Kou X, Zhao Y, He W, Li C, Chen B, Li Y, Wang Q, Ma J, Yin Q, Kee K, Meng A, Gao S, Xu F, Na J*, Xie W*. (2016). Allelic reprogramming of the histone modification H3K4me3 in early mammalian development. Nature 537(7621): 553-557.

Link to publication: doi: 10.1038/nature19361

Link to Pubmed: PMID: 27626382

18) Li L, Zhou X, Wang X, Wang J, Zhang W, Wang B, Cao Y*, Kee K*. (2016). A dominant negative mutation at the ATP binding domain of AMHR2 is associated with a defective anti-Mullerian hormone signaling pathway. Mol Hum Reprod 22(9): 669-678.

Link to publication: doi:10.1093/molehr/gaw040

Link to Pubmed: PMID: 27430550

19) Lin J, Chen H, Luo L, Lai Y, Xie W, Kee K*. (2015). Creating a monomeric endonuclease TALE-I-SceI with high specificity and low genotoxicity in human cells. Nucleic Acids Res 43(2): 1112-1122.

Link to publication: doi: 10.1093/nar/gku1339

Link to Pubmed: PMID: 25541197

20) Nguyen HN, Byers B, Cord B, Shcheglovitov A, Byrne J, Gujar P, Kee K, Schüle B, Dolmetsch RE, Langston W, Palmer TD*, Pera RR*. (2011). LRRK2 mutant iPSC-derived DA neurons demonstrate increased susceptibility to oxidative stress. Cell Stem Cell 8(3): 267-280.

Link to publication: doi: 10.1016/j.stem.2011.01.013

Link to Pubmed: PMID: 21362567

21) Kee K*, Flores M, Cedars MI, Reijo Pera RA*. (2010). Human primordial germ cell formation is diminished by exposure to environmental toxicants acting through the AHR signaling pathway. Toxicol Sci 117(1): 218-224.

Link to publication: doi: 10.1093/toxsci/kfq179

Link to Pubmed: PMID: 20562217

22) Kee K, Pera RA, Turek PJ*. (2010). Testicular germline stem cells. Nat Rev Urol 7(2): 94-100.

Link to publication: doi: 10.1038/nrurol.2009.263

Link to Pubmed: PMID: 20084076

23) Kee K, Angeles VT, Flores M, Nguyen HN, Reijo Pera RA*. (2009). Human DAZL, DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation. Nature 462(7270): 222-225.

Link to publication: doi: 10.1038/nature08562

Link to Pubmed: PMID: 19865085

24) Kee K, Reijo Pera RA*. (2008). Human germ cell lineage differentiation from embryonic stem cells. CSH Protoc 2008: pdb prot5048.

Link to publication: doi: 10.1101/pdb.prot5048

Link to Pubmed: PMID: 21356917

25) International Stem Cell Initiative (2007). Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat Biotechnol 25(7): 803-816.

Link to publication: doi:10.1038/nbt1318

Link to Pubmed: PMID: 17572666

26) Kee K, Gonsalves JM, Clark AT, Pera RA*. (2006). Bone morphogenetic proteins induce germ cell differentiation from human embryonic stem cells. Stem Cells Dev 15(6): 831-837.

Link to publication: doi: 10.1089/scd.2006.15.831

Link to Pubmed: PMID: 17253946

27) Henderson KA, Kee K, Maleki S, Santini PA, Keeney S*. (2006). Cyclin-dependent kinase directly regulates initiation of meiotic recombination. Cell 125(7): 1321-1332.

Link to publication: doi: 10.1016/j.cell.2006.04.039

Link to Pubmed: PMID: 16814718

28) Kee K, Protacio RU, Arora C, Keeney S*. (2004). Spatial organization and dynamics of the association of Rec102 and Rec104 with meiotic chromosomes. EMBO J 23(8): 1815-1824.

Link to publication: doi: 10.1038/sj.emboj.7600184

Link to Pubmed: PMID: 15044957

29) Arora C, Kee K, Maleki S, Keeney S*. (2004). Antiviral protein Ski8 is a direct partner of Spo11 in meiotic DNA break formation, independent of its cytoplasmic role in RNA metabolism. Mol Cell 13(4): 549-559.

Link to publication: doi: 10.1016/s1097-2765(04)00063-2

Link to Pubmed: PMID: 14992724

30) Kee K, Keeney S*. (2002). Functional interactions between SPO11 and REC102 during initiation of meiotic recombination in Saccharomyces cerevisiae. Genetics 160(1): 111-122.

Link to publication: doi: 10.1093/genetics/160.1.111

Link to Pubmed: PMID: 11805049

31) Kee K, Niu L, Henderson E*. (1998). A Tetrahymena thermophila G4-DNA binding protein with dihydrolipoamide dehydrogenase activity. Biochemistry 37(12): 4224-4234.

Link to publication: doi: 10.1021/bi9716377

Link to Pubmed: PMID: 9521745