ZBTB21 is a zinc finger and BTB domain-containing transcription factor that functions as a transcriptional repressor with context-dependent regulatory roles 1. Primary Function: ZBTB21 acts as a DNA-binding transcription factor capable of both repression and activation depending on target promoters 2. It binds to cAMP-response elements (CRE) and competes with CRE-binding factors like CREB to suppress CRE-dependent gene expression 1. Mechanism: ZBTB21 cooperates with ZBTB14 during early embryonic development to regulate anterior-posterior axis patterning by promoting posterior neural tissue formation 3. At the chr21 level, ZBTB21 contributes to cohesin binding and 3D chr21 interactions, working with other ZBTB factors to orchestrate chr21 organization 4. Its transcriptional activity is modulated by SUMOylation at conserved lysine residues 2. Disease Relevance: ZBTB21 is a chromosome 21-encoded gene contributing to Down syndrome pathology. Overexpression of ZBTB21 in Down syndrome impairs synaptic function and cognitive performance by suppressing CRE-mediated transcription of genes essential for synaptic plasticity and learning 1. Clinical Significance: ZBTB21 variants are associated with daytime napping in large-scale exome studies 5, suggesting roles in sleep-related phenotypes. Normalizing ZBTB21 gene dosage in Down syndrome models corrects cognitive deficits and synaptic dysfunction 1.