Hypothesis 1: Integrated stress response transcription factors ATF4 and DDIT3/CHOP suppress MAPT indirectly by reprogramming neuronal transcription toward proteostasis and amino-acid stress genes, possibly through promoter competition or recruitment of repressive chromatin regulators. Test: ATF4/CHOP occupancy, CRISPRi, and MAPT nascent transcript measurements during proteotoxic stress.
Hypothesis 2: HSF1 is the primary mediator; during proteostatic stress it diverts the transcriptional apparatus toward heat-shock targets and may actively recruit co-repressors at the MAPT locus to reduce tau production while chaperone capacity is restored. Test: HSF1 ChIP, acute HSF1 activation, and co-repressor mapping at MAPT enhancers.
Hypothesis 3: REST-like neuronal silencing programs are re-engaged during severe proteostatic stress and suppress MAPT as part of a broader synaptic downscaling state. This would predict coordinated repression of neuronal identity genes, not MAPT alone. Test: single-cell RNA-seq and REST perturbation under tunicamycin/proteasome inhibition conditions.