"Basic helix-loop-helix family, member e41", or BHLHE41, is a gene that encodes a basic helix-loop-helix transcription factor repressor protein in various tissues of both humans and mice. It is also known as DEC2, hDEC2, and SHARP1, and was previously known as "basic helix-loop-helix domain containing, class B, 3", or BHLHB3. BHLHE41 is known for its role in the circadian molecular mechanisms that influence sleep quantity as well as its role in immune function and the maturation of T helper type 2 cell lineages associated with humoral immunity.

Klaus-Armin Nave's lab identified BHLHE41/SHARP1 and BHLHE40/SHARP2 as a novel subfamily in the basic helix-loop-helix (BHLH) protein family. They differentiated BHLHE41/SHARP1 and BHLHE40/SHARP2 from other BHLH-protein encoding genes since they are not transcribed until the end of embryonic development. The DNA sequence of BHLHE41 was first obtained by Dr. Yukia Kato's lab through a cDNA library search. Particularly, they obtained the sequence of BHLHE40/DEC1 and conducted an expressed sequence tag (EST) search to identify the BHLHE41/DEC2 sequence. BHLHE41/DEC2 and BHLHE40/DEC1 share 97% homology in the BHLH domain. After the identification of the BHLHE41 gene, Dr. Ken-Ichi Honma's lab characterized its role as a regulator in the mammalian circadian clock. The role of BHLHE41 in other pathways is still being fully characterized.

BHLHE41 is a member of the DEC subfamily within the basic helix-loop-helix (bHLH) proteins gene family. BHLHE41 was mapped to human chromosome 12: 26,120,026-26-125-127 reverse strand and has a total length of 5,101 base pairs. The gene is also mapped to 6 G2-G3 on the mouse chromosome, and 4q43 distal-q4 on the rat chromosome respectively. BHLHE41 has 3 known splice variants. BHLHE41-002 and BHLHE41-003 are retained introns and do not code for a protein. BHLHE41-001 contains 5 coding exons, has a transcript length of 3,837 base pairs, and encodes the 482 amino acid BHLHE41 protein.[1] BHLHE40 is the paralogue of BHLHE41. BHLHE41 currently has 165 known orthologs.[2]

The BHLHE41 protein has a myc-type, basic helix-loop-helix (bHLH) domain and an orange domain. The orange domain is a 30 residue sequence located on the carboxy-terminal end relative to the BHLH domain of the protein whose function is still unclear. The basic helix-loop-helix domain allows members of the protein family to dimerize with each other to affect gene transcription through binding to specific DNA sequences. BHLHE41 protein also has alanine and glycine-rich regions in the C-terminal, and lacks the WRPW motif for interaction with the corepressor Groucho.

BHLHE41 recruits the histone methyltransferase G9a and histone deacetylases HDAC1 and Sirt1 to mediate chromatin modifications that repress target gene expression.

BHLHE41 is expressed in the suprachiasmatic nucleus with levels peaking during subjective day. The gene encodes for a transcription factor that belongs to the Hairy/Enhancer of Split (Hes) subfamily of basic helix-loop-helix factor genes which encode transcriptional repressors that function as downstream targets to regulate cell fate during tissue development. BHLHE41 acts as a transcriptional repressor and as a regulator of the Circadian clock. In the clock, the transcriptional factors Clock and Bmal form a heterodimer. This heterodimer binds to the E-Box promoter element, thereby promoting transcription of downstream genes such as Per and BHLHe41. After transcription and translation, the protein product of BHLHE41 (DEC2) reenters the nucleus and competes with Clock-Bmal1 heterodimer for E-Box element binding (through competitive inhibition); this acts as a suppressor for per gene transcription.

BHLHE41 has also been implicated in multiple other pathways. Deregulation of BHLHE41 transcription levels has been characterized as a marker in the progression of several cancers. Low levels of BHLHE41 transcript has been associated with tumor growth suggesting that BHLHE41 suppresses tumor proliferation; however, no definite mechanism of action has been discovered. Dec2 has also been hypothesized to be involved in the regulation of immune responses. Further research on characterizing these pathways and BHLHE41's specific role is still being conducted.

In mice lacking SHARP1/BHLHE41 and SHARP2, IGF-2 is elevated and leads to enhanced memory consolidation.