Reciprocal regulation between autism risk gene POGZ and circadian clock

Mar 17, 2026JCI insight

Two-Way Interaction Between Autism Risk Gene POGZ and the Body’s Internal Clock

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Pogz-deficient mice exhibited prolonged circadian periodicity and impaired light-induced phase shifts.

The ASD risk gene POGZ is widely expressed in the suprachiasmatic nucleus, which regulates circadian rhythms.
Pogz shows circadian oscillations in the hypothalamus and liver, with its transcription regulated by the circadian molecule DBP.
Pogz deletion in mice leads to reduced activation of a specific brain region in response to light.
POGZ enhances the activity of CREB, a key factor in resetting the circadian clock in response to light.
Cognitive impairments in Pogz-deficient mice are influenced by light exposure and the type of behavioral tests used.

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Sleep disturbance is a prevalent yet poorly understood comorbidity in autism spectrum disorders (ASD). Here, we uncover a bidirectional regulatory axis connecting the ASD risk gene POGZ to core circadian mechanisms. We demonstrate that Pogz is widely expressed in the suprachiasmatic nucleus (SCN), the central pacemaker of the circadian rhythms and exhibits circadian oscillations in both the hypothalamus and liver with its transcription directly regulated by the circadian molecule DBP through a D-box element in its proximal enhancer. Pogz-deficient mice exhibited prolonged circadian periodicity, impaired light-induced phase shift, delayed adaption to an 8-hour advance jet-lag, and reduced SCN c-Fos activation in response to light pulses. Mechanistically, POGZ interacts with and enhances the transcription activity of CREB, a key regulator of light-induced phase resetting. Notably, Pogz deletion leads to ASD-related deficits in social novelty and cognition, with cognitive impairments influenced by both photoperiod and behavioral paradigm. Our findings thus reveal a critical, previously unrecognized intersection between an ASD risk gene and circadian clock, offering new insights into the pathogenesis of core ASD symptoms and comorbid sleep disturbances.

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Reciprocal regulation between autism risk gene POGZ and circadian clock

Abstract

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