The Laetoli footprints made by humans 3.6 million years ago in Tanzania are perhaps the most famous footprints of all time. However, more recent footprints have been uncovered by the laboratories of Yechiel Elkabetz and Alexander Meissner. These epigenetic footprints represent each “step” in the process of neuronal differentiation from human embryonic stem cells (hESCs), and allow a deeper understanding of early human development, and possibly even the generation of specific progenitor cells with differing therapeutic values.
Ziller et al began by isolating six consecutive ESC-derived neural progenitor cell (NPC) stages based on Notch signaling (major pathway involved in NPC development) to model cell-fate decisions. The group assessed each stage at the transcriptional level (RNA-seq), and the epigenetic level (histone modifications and DNA methylation). This generated an epigenetic footprint for each stage that, using a computational framework developed by the researchers, could then be linked to the actions of specific transcription factor combinations through the assessment of DNA binding motifs associated with the epigenetic changes
From these analyses they uncovered that:
- certain core neurally-associated transcription factors interacted with stage-specific factors to mediate the specific epigenetic footprints distinguishing one stage from the next.
- 110 of the 244 transcription factors assessed had significant roles in stage-specific progenitor production, as determined by siRNA.
Further assessment also underlined an important role for a phenomenon known as epigenetic priming – the gain of H3K4me1 and loss of DNA methylation at transcription factor binding sites at the early NPC stages before increased expression of their associated genes in more differentiated cell types. The authors confirmed this through the assessment of NEUROD family binding sites associated with such an epigenetic pattern in NPCs, finding associated genes to be more highly expressed at later time points.
While this huge amount of data will no doubt shed light on the intricate goings-on during neural development, this strategy also represents a highly versatile system which can be used to dissect regulatory circuits of differentiation in other stem/progenitor cell lineages and to understand how epigenetic patterns serve to specify certain lineages.
So please, get those feet moving and Walk this Way to read the exciting new study in Nature, December 2014.