The PHD Domain of Np95 (mUHRF1) Is Involved in Large-Scale Reorganization of Pericentromeric Heterochromatin

Heterochromatic chromosomal regions undergo large-scale reorganization and progressively aggregate, forming chromocenters. These are dynamic structures that rapidly adapt to various stimuli that influence gene expression patterns, cell cycle progression, and differentiation. Np95-ICBP90 (m- and h-UHRF1) is a histone-binding protein expressed only in proliferating cells. During pericentromeric heterochromatin (PH) replication, Np95 specifically relocalizes to chromocenters where it highly concentrates in the replication factories that correspond to less compacted DNA. Np95 recruits HDAC and DNMT1 to PH and depletion of Np95 impairs PH replication. Here we show that Np95 causes large-scale modifications of chromocenters independently from the H3:K9 and H4:K20 trimethylation pathways, from the expression levels of HP1, from DNA methylation and from the cell cycle. The PHD domain is essential to induce this effect. The PHD domain is also required in vitro to increase access of a restriction enzyme to DNA packaged into nucleosomal arrays. We propose that the PHD domain of Np95-ICBP90 contributes to the opening and/or stabilization of dense chromocenter structures to support the recruitment of modifying enzymes, like HDAC and DNMT1, required for the replication and formation of PH

What is normal? A historical survey and neuroanthropological perspective

What is considered typical and usual is guided by the cultural framework a person is accustomed to. In the brain sciences, it can easily be forgotten that "normal" and "normality" are not rock solid concepts. Simply acknowledging that "normal" does not have an objective existence is insufficient without also changing scientific practices accordingly. This chapter unpacks why normality has been such a persistent concept for the last two centuries. The concept of normality grew alongside the development of statistical methods and was instrumental in constructing a much maligned concept of "degeneration." Statistics are useful in a wide range of scientific contexts, but detrimental when used as a blunt instrument of measurement to legitimize labels that differentially sort people into subpopulations that augment social inequalities. A rigorous questioning of normality and degeneration ensures an ethical engagement with hypotheses of neuroscience experiments and the implications of research findings. This chapter surveys some of the key historical developments at the origins of the brain sciences to understand some of the biases present today. The language used to classify the world can lead to blind spots that remain hidden for generations. Rather than searching for a direct localization of human behavior in biological etiology, this chapter advocates a complex localization through mapping distributed agency across intersecting neurobiological, cultural, and environmental processes. Normal might be a value-laden term that has no place in the brain sciences, but a value-free operational conceptualization of the processes of degeneracy may be central to understanding dynamic neuro-cultural systems.21 page(s