DataVXAdvanced SciencePaper
journal article·2025-12Open access

Pathogenicity of Mediator Complex Subunit 27 ( MED27 ) in a Neurodevelopmental Disorder with Cerebellar Atrophy

Nuermila Yiliyaer, Xiaocheng Li, Tianyu Guo, Haiying Zhou, Lihai Gong, Luowei Yuan, Yang Fu, Yulong Qiao, Ying Lam Lui, Nuo Chen, Pengfei Lin, Hoi Hung Cheung, Ho Ko, Linyan Meng, Xiao Chen, Yong Lei, Kin Ming Kwan, Huating Wang, Shen Gu

Advanced Science· Volume 12· Issue 48
Publisher pageOpen full text
Source abstract

Abstract

Abstract Neurodevelopmental disorders (NDDs) affect brain function and development, with 90% lacking approved treatments. Understanding their pathogenic mechanisms is critical for developing precision gene therapies. An autosomal recessive NDD associated with variants in the Mediator complex subunit 27 ( MED27 ) gene is previously identified. The Mediator complex is essential for transcription initiation by bridging transcription factors (TFs) at enhancers to RNA polymerase II at promoters. All patients with MED27 variants exhibit cerebellar hypoplasia or atrophy, underscoring the cerebellum's heightened vulnerability to MED27 dysfunction. To investigate the disease mechanisms, in vitro stem cells carrying patient‐specific MED27 variants and in vivo mouse models with Med27 loss‐of‐function (LoF) are generated. These preclinical models recapitulate key patient phenotypes, including progressive cerebellar atrophy and motor deficits. Molecular analyses reveal that mutant MED27 destabilizes the Mediator complex, impairing its chromatin occupancy and altering chromatin interactions. Comprehensive transcriptomic profiling, including single‐cell resolution spatial transcriptomics, identifies dysregulation of downstream targets regulated by MED27 , such as critical master regulatory TFs involved in neurogenesis and cerebellar development. This study elucidates a partial LoF mechanism underlying MED27 ‐associated NDDs and establishes a prototype for investigating NDDs caused by pathogenic variants in Mediator subunits.
Source: crossref · Quality: baseline

Research context

Polymers

OpenAlex topics: RNA modifications and cancer · RNA Research and Splicing · Genomics and Chromatin Dynamics

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

School of Biomedical Sciences Faculty of Medicine The Chinese University of Hong Kong (CUHK) Hong Kong SAR China

Gerald Choa Neuroscience Institute CUHK Hong Kong SAR China

School of Medicine CUHK (Shenzhen) Shenzhen Guangdong 518172 China

Department of Orthopaedics and Traumatology Li Ka Shing Institute of Health Sciences CUHK Hong Kong SAR China

Center for Neuromusculoskeletal Restorative Medicine Limited Hong Kong Science Park Hong Kong SAR China

School of Life Sciences CUHK Hong Kong SAR China

Department of Neurology and Research Institute of Neuromuscular and Neurodegenerative Diseases Qilu Hospital of Shandong University Jinan Shandong 250012 China

Division of Neurology Department of Medicine and Therapeutics & Li Ka Shing Institute of Health Sciences Faculty of Medicine CUHK Shatin Hong Kong China

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX 77030 USA

Baylor Genetics Houston TX 77021 USA

Department of Sports Medicine and Orthopedic Surgery of The Second Affiliated Hospital and Liangzhu Laboratory Zhejiang University School of Medicine Hangzhou 310000 China

Dr. Li Dak Sum‐Yip Yio Chin Center for Stem Cells and Regenerative Medicine Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China

Center for Cell and Developmental Biology CUHK Hong Kong SAR China

State Key Laboratory of Agrobiotechnology (CUHK) Hong Kong SAR China

CUHK Shenzhen Research Institute Shenzhen 518063 China

Key Laboratory for Regenerative Medicine Ministry of Education School of Biomedical Sciences Faculty of Medicine CUHK Hong Kong SAR China

Kunming Institute of Zoology‐The Chinese University of Hong Kong (KIZ‐CUHK) Joint Laboratory of Bioresources and Molecular Research of Common Diseases Hong Kong SAR China

Funding

National Natural Science Foundation of China · Guangdong Provincial Pearl River Talents Program · Shenzhen Science and Technology Innovation Program · Basic and Applied Basic Research Foundation of Guangdong Province · Science and Technology Planning Project of Guangdong Province

References (72)

Show source-provided references
1. 10.1126/science.abg063510.1126/science.abg0635 ↗
2. 10.1038/s41586-021-03555-710.1038/s41586-021-03555-7 ↗
3. 10.1038/s41580-022-00498-310.1038/s41580-022-00498-3 ↗
4. 10.1038/s41588-020-0635-010.1038/s41588-020-0635-0 ↗
5. 10.1016/j.cell.2019.07.01110.1016/j.cell.2019.07.011 ↗
6. 10.1038/nature0938010.1038/nature09380 ↗
7. 10.1161/CIRCRESAHA.122.32153210.1161/CIRCRESAHA.122.321532 ↗
8. 10.1016/j.celrep.2021.10931410.1016/j.celrep.2021.109314 ↗
9. 10.1002/ana.2601910.1002/ana.26019 ↗
10. 10.1016/j.gim.2022.07.01310.1016/j.gim.2022.07.013 ↗
11. 10.1093/brain/awad25710.1093/brain/awad257 ↗
12. 10.1038/nbt.417210.1038/nbt.4172 ↗
13. 10.1038/nprot.2013.14310.1038/nprot.2013.143 ↗
14. 10.1016/j.jhazmat.2020.12244010.1016/j.jhazmat.2020.122440 ↗
15. 10.1016/j.scr.2023.10315810.1016/j.scr.2023.103158 ↗
16. 10.1038/s41467-017-00668-410.1038/s41467-017-00668-4 ↗
17. 10.3389/fnana.2018.0010410.3389/fnana.2018.00104 ↗
18. 10.1016/j.cell.2013.09.05310.1016/j.cell.2013.09.053 ↗
19. 10.1038/s41467-019-10502-810.1038/s41467-019-10502-8 ↗
20. 10.3389/fnbeh.2017.0003510.3389/fnbeh.2017.00035 ↗
21. 10.1016/j.molcel.2020.06.00710.1016/j.molcel.2020.06.007 ↗
22. 10.14348/molcells.2020.020710.14348/molcells.2020.0207 ↗
23. 10.1016/j.stem.2019.09.01010.1016/j.stem.2019.09.010 ↗
24. 10.3390/cells1402014310.3390/cells14020143 ↗
25. 10.1016/j.molcel.2005.02.01010.1016/j.molcel.2005.02.010 ↗
26. 10.4161/trns.2287410.4161/trns.22874 ↗
27. 10.1093/hmg/ddx09910.1093/hmg/ddx099 ↗
28. 10.1126/science.120663810.1126/science.1206638 ↗
29. 10.1038/nrg.2016.11210.1038/nrg.2016.112 ↗
30. 10.1101/gr.257832.11910.1101/gr.257832.119 ↗
31. 10.1126/sciadv.abg820510.1126/sciadv.abg8205 ↗
32. 10.1038/s41588-023-01364-410.1038/s41588-023-01364-4 ↗
33. 10.1186/s13059-020-02167-010.1186/s13059-020-02167-0 ↗
34. 10.1530/REP-18-050810.1530/REP-18-0508 ↗
35. 10.1371/journal.pone.014019210.1371/journal.pone.0140192 ↗
36. 10.1523/JNEUROSCI.4385-15.201610.1523/JNEUROSCI.4385-15.2016 ↗
37. 10.1242/dev.126.16.358510.1242/dev.126.16.3585 ↗
38. 10.1242/dev.18558710.1242/dev.185587 ↗
39. 10.1007/s12311-015-0724-210.1007/s12311-015-0724-2 ↗
40. 10.1038/s41586-023-06884-x10.1038/s41586-023-06884-x ↗
41. 10.1002/1526-968X(200011/12)28:3/4<93::AID-GENE10>3.0.CO;2-W10.1002/1526-968X(200011/12)28:3/4<93::AID-GENE10>3.0.CO;2-W ↗
42. 10.1007/s12311-016-0770-410.1007/s12311-016-0770-4 ↗
43. 10.7554/eLife.6366810.7554/eLife.63668 ↗
44. 10.3389/fnana.2012.0001110.3389/fnana.2012.00011 ↗
45. 10.1016/0304-3940(82)90380-910.1016/0304-3940(82)90380-9 ↗
46. 10.1016/j.neuron.2004.10.03110.1016/j.neuron.2004.10.031 ↗
47. 10.1016/j.neuron.2023.10.03910.1016/j.neuron.2023.10.039 ↗
48. 10.1038/s41586-021-03220-z10.1038/s41586-021-03220-z ↗
49. 10.1038/s41587-021-00830-w10.1038/s41587-021-00830-w ↗
50. 10.1111/dgd.1260910.1111/dgd.12609 ↗
51. 10.1073/pnas.070546410410.1073/pnas.0705464104 ↗
52. 10.1038/ncomms1507910.1038/ncomms15079 ↗
53. 10.1038/nature1399210.1038/nature13992 ↗
54. 10.1523/JNEUROSCI.23-04-01310.200310.1523/JNEUROSCI.23-04-01310.2003 ↗
55. 10.1534/genetics.105.05515210.1534/genetics.105.055152 ↗
56. 10.1534/g3.114.01412610.1534/g3.114.014126 ↗
57. 10.7554/eLife.3870910.7554/eLife.38709 ↗
58. 10.1111/dgd.1263110.1111/dgd.12631 ↗
59. 10.1016/j.cell.2013.03.03510.1016/j.cell.2013.03.035 ↗
60. 10.1016/j.lfs.2024.12302010.1016/j.lfs.2024.123020 ↗
61. 10.1007/s10048-021-00661-610.1007/s10048-021-00661-6 ↗
62. 10.1007/s00439-015-1541-x10.1007/s00439-015-1541-x ↗
63. 10.1073/pnas.112112010910.1073/pnas.1121120109 ↗
64. Smol T. · HGG Adv. · 2025 · 6
65. 10.3389/fnmol.2011.0000610.3389/fnmol.2011.00006 ↗
66. 10.1093/nar/gkt83710.1093/nar/gkt837 ↗
67. 10.1101/gad.348471.12110.1101/gad.348471.121 ↗
68. 10.1038/s41596-021-00651-w10.1038/s41596-021-00651-w ↗
69. 10.1038/s41596-023-00817-810.1038/s41596-023-00817-8 ↗
70. 10.1126/science.aar419910.1126/science.aar4199 ↗
71. 10.1038/s41586-019-1464-010.1038/s41586-019-1464-0 ↗
72. 10.1038/s41580-021-00362-w10.1038/s41580-021-00362-w ↗