2. Academic Validation
  3. ZBTB21 suppresses CRE-mediated transcription to impair synaptic function in Down syndrome

ZBTB21 suppresses CRE-mediated transcription to impair synaptic function in Down syndrome

  • Sci Adv. 2024 Jul 5;10(27):eadm7373. doi: 10.1126/sciadv.adm7373.
Muzhen Qiao 1,  Qianwen Huang 1,  Xin Wang 2 3,  Jiahuai Han 1 3 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
  • 2 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Department of Neurology, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361002, China.
  • 3 Laboratory Animal Center, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
  • 4 Research Unit of Cellular Stress of CAMS, Xiang'an Hospital of Xiamen University, Cancer Research Center of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
PMID: 38959316 DOI: 10.1126/sciadv.adm7373
Abstract

Down syndrome (DS) is the most common chromosomal disorder and a major cause of intellectual disability. The genetic etiology of DS is the extra copy of chromosome 21 (HSA21)-encoded genes; however, the contribution of specific HSA21 genes to DS pathogenesis remains largely unknown. Here, we identified ZBTB21, an HSA21-encoded zinc-finger protein, as a transcriptional repressor in the regulation of synaptic function. We found that normalization of the Zbtb21 gene copy number in DS mice corrected deficits in cognitive performance, synaptic function, and gene expression. Moreover, we demonstrated that ZBTB21 binds to canonical cAMP-response element (CRE) DNA and that its binding to CRE could be competitive with CRE-binding factors such as CREB. ZBTB21 represses CRE-dependent gene expression and results in the negative regulation of synaptic plasticity, learning and memory. Together, our results identify ZBTB21 as a CRE-binding protein and repressor in cAMP-dependent gene regulation, contributing to cognitive defects in DS.

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