Histone deacetylase HDAC4/5 cooperates with cAMP response element-binding protein (CREB) in the transcriptional regulation of daily sleep amount downstream of LKB1-SIK3 kinase cascade in mice. Here, we report a significant enrichment of the E-box motifs for the basic loop-helix-loop (bHLH) proteins near the CREB- and HDAC4-binding sites in the mouse genome. Adeno-associated virus (AAV)-mediated expression of class I bHLH transcription factors, such as TCF4, TCF3, or TCF12, across the mouse brain neurons reduces the duration of rapid eye movement sleep (REMS) and non-REMS (NREMS). TCF4 requires its bHLH domain to regulate REMS or NREMS amount, of which the latter is mostly independent of the E-box-binding activity. Consistent with that TCF4 interacts with CREB and HDAC4 via the bHLH domain, TCF4 relies on CREB and partly on HDAC4 to regulate NREMS/REMS amount. Conversely, the ability of CREB to regulate sleep duration also requires its binding to TCF4 and HDAC4. Together, these results indicate that TCF4, HDAC4, and CREB could function cooperatively in the transcriptional regulation of daily sleep amount in mice.
Keywords: CREB; HDAC4; TCF4; basic loop-helix-loop (bHLH); non-rapid eye movement sleep (NREMS); sleep amount.
© The Author(s) 2025. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.