For decades, scientists have been attempting to unravel the transcriptional programs that give rise to the wide variety of neuronal cell types that collectively make up the central nervous system. Several transcription factors were shown to play key roles in neurogenesis and neuronal diversification (for an extensive review see [
14]). For instance, the expression of
Dlx1 (distal-less homeobox 1) and
Dlx2 counteracts the expression of
Olig1 (oligodendrocyte transcription factor 1) and
Olig2 to promote interneuron fate over oligodendrocyte specification and vice versa [
15,
16]. Furthermore, upregulation of the transcription factor
Pax6 (paired box 6) induces neurogenesis through induction of
Ngn2 (neurogenin 2) [
17]. Surprisingly, overexpression of
Pax6 could also induce neurogenesis in post-natal astrocytes
in vitro, representing one of the earliest examples of lineage conversion directed by a single transcription factor [
18].
Ngn2 as well as
Ascl1 (achaete-scute homolog 1), another key factor in neurogenesis, was also shown to be able to drive neuronal cell fate specification in post-natal astrocytes suggesting that differentiation boundaries could be overcome using specific transcription factors [
19]. Following these discoveries, select combinations of transcription factors were identified that, when overexpressed, were able to induce major cell state changes [
8]. This included the direct conversion of fibroblasts into neuronal cell types [
20], which has now been achieved through overexpression of different combinations of neuronal transcription factors, typically using
Ascl1 as a cornerstone factor (reviewed in [
21]). These data demonstrate that transcription factors play a central role in determining cell state specification in the nervous system as well as in controlling the plasticity of these states.
Following the emergence of genome-scale transcriptome analyses, spatio-temporal gene expression programs in the brain are now rapidly being elucidated. Large consortia, including the Allen Institute for Brain Science and
BrainSpan, have collected gene expression data in murine and human tissues at different developmental stages as well as in brain tissue from humans suffering from neurological disorders [
22,
23]. Furthermore, co-expression analysis of these types of data has revealed a hierarchical structure of networks in which certain transcription factors present as central (hub) genes that modulate the expression of other genes [
22,
24,
25]. For instance,
TBR1 (T-brain 1) and
EMX2 (empty spiracles homeobox 2) have emerged as hub regulators in the adult human brain [
25] and are well-known cortical transcription factors involved in state specification of cortical progenitors and adult neurons [
26]. While these analyses are starting to reveal the hierarchal structure of gene regulatory networks, a full grasp of their complexity can only be achieved when combined with intricate knowledge of the underlying CREs to which these transcription factors bind. The latter analysis has until recent years been lagging behind.