Hi! I have not done ChIP assay, but I have sliced non-perfused brains at 200um for westerns. I think you should be able to slice 300um, so I have some suggestions. Are you slicing on a cryostat? If so, you can try lifting the protective glass ever so slightly as you are slicing, to have the tissue slice without it bunching up beneath the glass. Another option is to embed the brain with more glue (e.g., if doing coronal section, don't just cover the cerebellum, cover up to the cortex near where you need to slice). By securing the brain it should allow you to get better sections. (Remember to use a new blade also, of course). I hope that helps!

From what I understand, the extent of cross-linking achieved by transcardial perfusion with 4% paraformaldehyde is much greater than what is desired of that in the cross-linking step for ChIP (which in most protocols requires submerging the tissue in 1% para for around 15 min). If too much cross-linking has occurred then the antigen of interest can be made inaccessible, epitopes could be masked and antibody binding will be low and immunoprecipitation will be marginal. Fresh, frozen tissue is preferred because the cross-linking step is time-dependent and the addition of glycine to quench cross-linking is an important step that cannot be performed on previousy fixed tissue.

You might try a few things, 1) slice the tissue at a slightly warmer temp (perhaps -15 to -10 on a cryostat will reduce the brittle nature of the tissue and allow you to get a 300 um slice - you must give tissue time to come to this temp if being removed from -80 storage); 2) if possible, punch the tissue while it is still intact (i.e., slice to the desired plane, and punch into the tissue as it sits mounted on the cryo stage, making sure to keep the depth at 300um), 3) use a brain matrix to acquire a 500um slice to punch from, or 4) take the freshly removed brain tissue and slice fresh on a vibratome to the 300um thickness at the desired level, either snap freeze this slice and then punch, or punch carefully and then snap freeze the tissue punch.

I hope those suggestions help/make sense.

If you have the ability, then the vibratome would be the easiest, sections can be taken of any thickness and are easy to handle with a glass pipette that has been fire polished at the end. Just fill the bath with ice cold PBS to prevent degredatiobn.