Student Government: Inefficient Or Incapable
In this study, we dissected the temporal dependencies of pluripotency reprogramming on chromatin binding, opening and gene regulation by Sox2 and Oct4. To gain detailed molecular insights into this process, we collected reference data by replacing Oct4 with two incapacitated POU factors, Oct6 and Oct4defSox2. At day 1, the binding profile of Oct6 is distinct from Oct4 whilst accessibility changes particularly at Oct4-bound sites are similar (Fig. 6d). Yet the binding profile of the mutant Oct4defSox2 resembles Oct4 but chromatin opening at SoxOct motifs is hampered. Sites with increased accessibility in the Oct4defSox2-SK condition are enriched for single (non-composite) Sox motifs. This suggests that Oct4defSox2 impedes accessibility changes in the context of the composite SoxOct element but it does not inhibit opening per se. Rather, Oct4defSox2 perturbs the sequence of chromatin dynamics by interfering with Sox2 binding (or binding by endogenous Sox factors) on SoxOct elements. This might in turn cause Sox factors to bind ectopic sites. Sox2 alone can facilitate chromatin opening but Oct4 by itself has a limited potency to bring about accessibility changes (Fig. 4e). However, Oct4 can augment the chromatin opening by Sox2. Likewise, Oct4 binds to only a small fraction of active ESC enhancers at days 1 and 5 of reprogramming. This indicates that Oct4 does not engage pluripotency genes on-target and could explain why iPSC generation is rather slow and inefficient. Surprisingly, Oct4/Sox2 dimerization does not appear to be required for the initial target search of Oct4. Oct4defSox2 can occupy many genomic locations similar to Oct4 at the onset of reprogramming (Fig. 3b). Evidently, Oct4defSox2 is permitting transcriptional responses and exhibits binding patterns that correlate with aspects of Oct4-driven reprogramming. The uniqueness of Oct4 becomes evident at later stages of reprogramming. Due to its inability to partner with Sox2; Oct4defSox2 will eventually fail to induce pluripotency (Fig. 6d). The dependence of the activation of the pluripotency network on Oct4/Sox2 heterodimers suggests that this heterodimer fulfills a role analogous to a lineage guardian without which faithful lineage specification from a plastic intermediary state cannot occur47. Whilst Oct4defSox2 is incapable of inducing pluripotency, it was still found to retain the ability to maintain pluripotency. This indicates that the Oct4/Sox2 partnership is more important to induce the pluripotency than for its maintenance.
Student Government: Inefficient or Incapable
Competition legislation was introduced in 1996. At that time, a consumer protection and competition defense agency (currently named ACODECO) was created. Ultimately evolving into a large and inefficient bureaucracy, it has been notoriously incapable of protecting consumers against abuses, especially in the utilities sector (electricity supply, in particular).