Nucleosome remodelling and deacetylation (NuRD) is a chromatin remodelling complex with two distinct enzymatic activities: histone deacetylation by its subunits HDAC1 and HDAC2 and nucleosome remodelling by CHD4. The two NuRD modules are linked by MBD3. NuRD is widely distributed at sites of active transcription, where it controls nucleosome density at regulatory sequences. Bornelöv et al. investigated the individual enzymatic activities of NuRD and their roles in regulating transcription.

Genome-wide analysis of NuRD components mapped CHD4 and MBD3 predominantly to sites of active transcription, but surprisingly MBD3 depletion and consequently impairment of NuRD complex formation in mouse embryonic stem cells (mESCs) caused only modest changes in gene expression. This suggests that NuRD may be involved in fine-tuning, instead of acting as an on–off switch, of gene expression.

NuRD may be involved in fine tuning, instead of acting as an on–off switch, of gene expression

To study how NuRD regulates gene expression, the authors engineered inducible NuRD activation in mESCs by fusing MBD3 with the oestrogen receptor. Addition of the oestrogen-receptor ligand tamoxifen induced MBD3 translocation to the nucleus, NuRD complex formation and transcriptional changes and restored differentiation potential.

The addition of tamoxifen caused changes in histone acetylation only 48 h after MBD3-dependent formation of the NuRD complex on chromatin and after the occurrence of transcriptional changes. Conversely, changes in nucleosome positioning were observed shortly after NuRD complex formation. This suggests that the chromatin remodelling activity (and not the deacetylation activity) of NuRD is the primary cause of the observed transcriptional changes.

Intriguingly, NuRD-dependent increase in nucleosome density led to clearance of chromatin-bound proteins, which then allowed binding of a new set of proteins at these sites. Specific MBD3-dependent effects at promoters and enhancers also resulted in dissociation of the transcription machinery and transient reduction of nascent RNA levels, resulting in either increased or decreased gene expression.

Finally, NuRD maintained suitable nucleosome structure and protein binding at regulatory sequences of specific genes undergoing differentiation-induced transcriptional changes.

In summary, the data indicate that NuRD is capable of fine-tuning gene expression by modulating nucleosome density, leading to both gene activation and repression. The determinants of the different outcomes remain unclear.