The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.

HLA genotype affects response: Immunotherapy works by activating the patient's own immune system to fight cancer. For effective tumor killing, CD8 ⁺ T cells recognize tumor peptides presented by human leukocyte antigen class I (HLA-I) molecules. In humans, there are three major HLA-I genes ( HLA-A, HLA-B , and HLA-C ). Chowell et al. asked whether germline HLA-I genotype influences how T cells recognize tumor peptides and respond to checkpoint inhibitor immunotherapies (see the Perspective by Kvistborg and Yewdell). They examined more than 1500 patients and found that heterozygosity at HLA-I loci was associated with better survival than homozygosity for one or more HLA-I genes. Thus, specific HLA-I mutations could have implications for immune recognition and for the design of epitopes for cancer vaccines and immunotherapies. Science , this issue p. 582 ; see also p. 516

Outfoxing Immune Excess: Immune responses are kept in check by Foxp3-expressing CD4 ⁺ -regulatory T cells (T _regs ) through a variety of mechanisms. Expression of specific transcription factors directs T _reg responses into distinct T helper cell lineages; however, the transcription factors that regulate particular helper lineages have not been completely characterized. Chaudhry et al. (p. 986 , published online 1 October) show that the transcription factor Stat3, that is required for the initial differentiation of T _H 17-effector T cells, is also required for T _reg cell-mediated suppression of T _H 17-mediated immune responses. Mice carrying a T _reg cellspecific deletion in Stat3 succumb to an intestinal inflammatory disease driven by uncontrolled T _H 17 responses. Thus, different classes of immune responses can result from the expression of helper lineage–specific transcription factors.