Path Dependency in Cell State

A cell’s state is a result of the signals it currently receives from the environment and the cellular “memory” of the signals it received in the past. Multiple potential mechanisms — including chromatin modifications and feedback loops of transcription factors — may explain the stable propagation of “remembered” cellular states. However, little is known about how such states are formed in the first place. One property of remembered states is that they provide a path-dependence to cell state changes. To characterize how path-dependence emerges in cells, we will profile cells with different “histories” after they enter a shared final environment. In such an approach, path-dependent states will display persistent differences that specifically associate to cellular history (and not the signals in the final environment). These history-dependent differences may form when transcription factors activated by historical signals interact or compete with transcription factors activated by current signals.

We predict that a subset of transcription factors shapes history-dependent responses to cell signals. We may be able to identify these factors by measuring the differences in chromatin accessibility that result exclusively from differences in signal history. Using human breast carcinoma cells as a model system (MCF-7 cells), we will pre-treat cells with a distinct first signal before treating them with a shared second signal. Following at least two days in the common second signal, we will perform ATAC-seq on live cells from each pre-treatment condition. ATAC-seq uses Tn5 transposase to selectively fragment sterically accessible DNA in intact nuclei. We will sequence these fragments to find genomic locations where chromatin accessibility depends only on the historical signal environments for each condition. We will discuss preliminary data about the effect of historical signals on chromatin accessibility, as well as early analysis of transcription factor motif enrichment at such sites of history-dependent accessibility.